Disease and Glutathione

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Medical References

Alcohol Damage

Anthrax

Arthritis

Asthma, Bronchitis, and other Pulmonary and Respiratory Diseases

Autism Linked to Overactive Immune System, Study Finds

Cancer

Chrone's Disease and Digestive Disorders

Chronic Fatigue Syndrome

Cognitive Performance

Diabetes

Epilepsy and Seizures

Eyes and Macular Degneration

Gum Disease

HIV - AIDS

Heart (cardiovascular disease, cholesterol, atherosclerosis, stroke)

Hepatitis B and C

Immune System

Infertility

Influenza Infection

Kidney Disease

Lung Disease

Lupus

Meniere's Disease

Multiple Sclerosis

Neurodegenerative Diseases - Alzheimer's and Parkinson's Disease

Osteoporosis

Prostate

Additional Studies and References

Aging

Antioxidant Functions

Athletic Performance, Endurance and Sports Nutrition

Colostrum and our Bio-Active Protein Comparison

Healthy Elderly Women

Detoxification with GSH

Intravenous GSH, NAC, Cysteine, Methionine vs Immunocal

Maintaining Health

Pregnancy, Lactation and Childbirth

Toxins, Pollution and Radiation

GSH and Alcohol Damage

Efficacy of a whey protein concentrate on the inhibition of stomach ulcerative lesions caused by ethanol ingestion
Rosaneli CF, Bighetti AE, Antonio MA, Carvalho JE, Sgarbieri VC. [J Med Food. 2002 Winter;5(4):221-8.] The purpose of this research was to test the ability of a whey protein concentrate (WPC) to inhibit gastric mucosal ulcerative lesions caused by oral administration to rats of absolute ethanol. Acute administration (single doses) of WPC resulted in 41% inhibition of the ulcerative lesion index (ULI), and 73% inhibition was obtained with repetitive doses. In a 10-days subchronic treatment study, the inhibition was 64%, all relative to a saline treatment (negative control). Alkylation of sulfhydryl compounds by subcutaneous injection of N-ethylmaleimide essentially eliminated the WPC protection. Treating the rats with an intraperitoneal injection of butathionine sulfoximine, which inhibits glutathione synthesis, reduced WPC protection to 35% and 52% for single and double doses, respectively. Taken as a whole, the results indicate that WPC does protect gastric mucosa from ethanol damage and that the protection depends on sulfhydryl compounds present in the WPC, including its capacity to stimulate glutathione synthesis.

N-acetylcysteine attenuates alcohol-induced oxidative stress in the rat
Resat Ozaras, Veysel Tahan, Seval Aydin, Hafize Uzun, Safiye Kaya, Hakan Senturk [World J Gastroenterol 2003;9(1):125-128] There is increasing evidence that alcohol-induced liver damage may be associated with increased oxidative stress. We aimed to investigate free-radical scavenger effect of n-acetylcysteine in rats intragastrically fed with ethanol. In this study, we tested whether NAC attenuates alcohol-induced free radical damage in the liver in a rat model. Reactive oxygen intermediates contributes to the pathogenesis of various hepatic disorders such as paracetamol intoxication, hemochromatosis, toxic hepatitis, and alcoholic liver injury. Oxidative damage correlates with the amount of ethanol consumed. NAC provides protection from toxic liver damage by elevating intracellular glutathione concentrations.

Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity
Lauterburg BH and Velez ME. [Gut. 1998; volume 29, pages 1153-1157.] "The data indicate that low glutathione may be a risk factor for [acetaminophen] hepatotoxicity in alcoholics because a lower dose of [acetaminophen] will be necessary to deplete glutathione below the critical threshold concentration where hepatocellular necrosis starts to occur."

Ethanol Ingestion Impairs Alveolar Epithelial Glutathione Homeostasis and Function, and Predisposes to Endotoxin-Mediated Acute Lung Injury.
David Guidot, M. Moss, F. Holguin, M. Lois, L. Brown [Chest, July, 1999] Because ethanol impairs hepatic synthesis and secretion of glutathione (GSH), a critical antioxidant in the alveolar lining fluid, we hypothesized that alcohol abuse disrupts alveolar GSH homeostasis, and that the consequent epithelial dysfunction predisposes alcoholics to acute lung injury. These findings support a direct role for GSH depletion in ethanol-mediated susceptibility to lung injury. We conclude that long-term ethanol ingestion depletes alveolar epithelial mitochondrial GSH, thereby decreasing cell viability and function, and rendering the lung more vulnerable to acute edematous injury. We speculate that GSH replacement, particularly targeted to the mitochondrial pool, may decrease the severity of acute lung injury in alcoholic patients who are at risk for developing ARDS.

Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases
Lieber, C.S. [Adv. Pharmacol. 1997; 38: 601-28.]

Glutathione depletion in chronic alcohol abuse makes lungs vulnerable to life-threatening diseases
24 April, 2002; Emory University Health Sciences Center
Chronic alcohol abuse causes a profound deficiency of the antioxidant glutathione in the lungs, generating a marked susceptibility to serious lung diseases, according to research at Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center. Lowered glutathione levels can be as deadly to the lungs of alcohol abusers as alcohol itself can be to their livers and other organs, says David Guidot, M.D., associate professor of medicine at Emory University School of Medicine. The cure for alcohol-induced lung damage is not as simple as just taking extra doses of glutathione, Dr. Guidot points out, because an acute lung infection often is the first sign of damage. "If your house is on fire, it’s too late to install a smoke detector," he says. Glutathione depletion cannot be quickly reversed. Only after the immediate illness is addressed can physicians consider treating a patient for alcoholism and consider long-term glutathione therapy. By studying the mechanisms of glutathione damage, Dr. Guidot and his colleagues hope to design more effective therapies for preventing and treating the effects of chronic alcohol abuse.

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GSH and Anthrax

Role of macrophage oxidative burst in the action of anthrax lethal toxin
Hanna PC, Kruskal BA, Ezekowitz RA, Bloom BR, Collier RJ. [Mol Med 1994 Nov;1(1):7-18. PMID: 8790597] A Harvard Medical School study found that much of the toxic effect exerted by the anthrax organism was due to chemicals releasing high levels of free radicals. This was one of the factors causing cellular damage and death. Moreover, they found that raising glutathione provided partial protection against the toxins involved.

[Effect of the lethal Bacillus anthracis toxin on phagocytosis and the dynamics of the change in the enzyme activity of the antioxidative system of peritoneal mononuclear phagocytes in mice with differing hereditary immunity to anthrax]
Abalakin VA, Sorochinskaia EP, Osipova NI, Iurkiv VA. [Biull Eksp Biol Med 1989 Mar;107(3):288-91. PMID: 2496765] An earlier study done in Russia suggested that infected individuals with strong glutathione capabilities would do better against anthrax infection

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GSH and Arthritis

Impaired glutathione reductase activity and levels of collagenase and elastase in synovial fluid in rheumatoid arthritis.

Bazzichi L, Ciompi ML, Betti L, Rossi A, Melchiorre D, Fiorini M, Giannaccini G, Lucacchini A.

Rheumatic Diseases Unit, Medica Santa Chiara Hospital, University of Pisa, Pisa, Italy.

OBJECTIVE: To test the activity of elastase, collagenase and glutathione reductase in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) and in patients with osteoarthritis (OA); to correlate the elastase and collagenase activity with the glutathione reductase activity, which is important for the inactivation of oxygen free radicals. METHODS: 24 patients affected by osteoarthrosis and 24 patients affected by rheumatoid arthritis took part in the study. We measured elastase activity towards the substrate metoxysuccinyl-alanyl-alanyl-prolyl-valyl-p-nitroanilide (MeOSuc-ala-ala-proval-p-NA) which is highly specific for elastase, and insensitive to the other serine proteases, such as cathepsin G; collagenase activity was measured using [14C]-acetylated collagen as the substrate. Glutathione reductase activity was measured following the oxidation of nicotinamide adenine dinucleotide phosphate reduced (NADPH) in the presence of oxidized glutathione (GSSG). RESULTS: The concentrations of elastase, collagenase and glutathione reductase were statistically higher in patients with RA than in patients with OA. Moreover, in the SF of patients with RA we found positive correlation between enzyme activity levels. CONCLUSION: These results confirm a high activity of collagenase and elastase in the SF of patients with RA, which is about 30 times higher than that found in the SF of patients with OA. These data underline the synergic action of these enzymes in the pathogenesis of joint damage. RA patients also exhibit higher levels of glutathione reductase, which is important for the detoxification pathway of oxygen free radicals. However, compared with findings for collagenase and elastase, the increase in glutathione reductase is only three times higher than level found in the SF of OA patients. The limited increase in glutathione reductase activity during the inflammatory process might lead to an insufficient protective effect at the joint level in rheumatoid arthritis.

PMID: 12508766 [PubMed - indexed for MEDLINE]

J Appl Toxicol. 2001 Jan-Feb;21(1):69-73.

The glutathione defense system in the pathogenesis of rheumatoid arthritis.

Hassan MQ, Hadi RA, Al-Rawi ZS, Padron VA, Stohs SJ.

Faculty of Pharmacy & Medical Sciences, Amman University, Amman 19328, Jordan.

In order to assess a possible role of the natural glutathione defense system in the pathogenesis of rheumatoid arthritis (RA), serum reduced glutathione levels (GSH), glutathione reductase (GSR), glutathione S-transferase (GST), glutathione peroxidase (GSH-Px) and alkaline phosphatase (ALP) activities, lipid peroxidation (MDA content) and indexes of inflammation were evaluated in 58 rheumatic patients. Rheumatoid athritis was associated with significant depletion (ca. 50%) in GSH levels compared with normal control subjects. Serum levels of the detoxifying enzymes GSR and GSH-Px decreased by ca. 50% and 45%, respectively, whereas a threefold increase in the activity of GST was observed. A 1.2-fold increase in ALP was observed in patients with RA. These effects were accompanied by a 3.1-fold increase in serum MDA content. The MDA content was higher in RA patients who were seropositive for rheumatoid factor as well as positive for C-reactive proteins. The erythrocyte sedimentation rate for all patients with RA was approximately 13.8-fold higher than for the control group, and was higher among RA patients who were positive for C-reactive proteins and exhibited seropositivity for rheumatoid factor. Patients with RA receiving gold therapy exhibited significantly lower MDA levels whereas all other factors that were measured were not effected. The results support a hypothesis that defense mechanisms against reactive oxygen species are impaired in RA. Copyright 2001 John Wiley & Sons, Ltd.

PMID: 11180282 [PubMed - indexed for MEDLINE] Arthritis Rheum. 2003 Dec;48(12):3419-30.

Increased oxidative stress with aging reduces chondrocyte survival: correlation with intracellular glutathione levels.

Carlo MD Jr, Loeser RF.

Rush Medical College of Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.

OBJECTIVE: To examine the role of oxidative stress in mediating cell death in chondrocytes isolated from the articular cartilage of young and old adult human tissue donors. METHODS: Cell death induced by the oxidant SIN-1 was evaluated in the alginate bead culture system using fluorescent probes to assess membrane integrity. Generation of peroxynitrite by the decomposition of SIN-1 was confirmed by positive immunostaining of treated cells for 3-nitrotyrosine. Determinations of oxidized glutathione (GSSG) and reduced glutathione (GSH) were performed in monolayer cultures using an enzyme- recycling assay. Cells were depleted of intracellular glutathione either by the addition of DL-buthionine-(S,R)-sulfoximine or by removal of L-cystine from the culture media. The activity of cellular antioxidant enzymes was determined spectrophotometrically by the decay of substrate from the reaction mixture. RESULTS: More chondrocytes (>2-fold) from old donors (>/=50 years) died after exposure to 1 mM SIN-1 relative to those derived from young donors (18-49 years). Although autocrine production of insulin-like growth factor 1 (IGF-1) promotes chondrocyte survival, pretreatment with IGF-1 could not prevent the cell death induced by SIN-1 exposure. Cells isolated from old donors had a higher ratio of GSSG to GSH. Glutathione reductase is the principal enzyme involved in the regeneration of GSH from GSSG. Treatment of chondrocytes with SIN-1 to induce oxidative stress in vitro resulted in the decreased activity of glutathione reductase and thioredoxin reductase, but not catalase. Cells depleted of intracellular glutathione were more susceptible to cell death induced by SIN-1. CONCLUSION: These results provide evidence that increased oxidative stress with aging makes chondrocytes more susceptible to oxidant-mediated cell death through the dysregulation of the glutathione antioxidant system. This may represent an important contributing factor to the development of osteoarthritis in older adults.

PMID: 14673993 [PubMed - indexed for MEDLINE]

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GSH in Asthma, Bronchities and Other Pulmonary and Respiratory Diseases (COPD)

Glutathione: in defense of the lung.
Kelly FJ. [Food Chemistry Toxicology. 1999; volume 37, number 9-10, pages 963-966.] Oxidative stress is implicated in the pathology of numerous diseases of the lung. These include cystic fibrosis, chronic obstructive airway disease and asthma. The lung, like many other tissues, has a range of antioxidant defences which help to maintain a balanced redox status. These antioxidants are present in the intracellular, the vascular and extracellular respiratory tract lining fluid (RTLF) compartments. The reduced glutathione (GSH) content of RTLF is particularly high and new findings are beginning to reveal the role that the RTLF GSH pool plays in defending the lung.

Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis
Roum, James H., Zea Borok, Noel G. McElvaney, George J. Grimes, Allan D. Bokser, Roland Buhl and Ronald G. Crystal. [Journal of Applied Physiology 1999 Jul;87(1):438-43] Cystic fibrosis (CF) is characterized by accumulation of activated neutrophils and macrophages on the respiratory epithelial surface (RES); these cells release toxic oxidants, which contribute to the marked epithelial derangements seen in CF. These deleterious consequences are magnified since reduced glutathione (GSH), an antioxidant present in high concentrations in normal respiratory epithelial lining fluid (ELF), is deficient in CF ELF. To evaluate the feasibility of increasing ELF GSH levels and enhancing RES antioxidant protection, GSH aerosol was delivered to 7 individuals with CF. ELF total, reduced and oxidized glutathione increased suggesting adequate RES delivery and utilization of GSH. PMA-stimulated superoxide anion (O2.) release by ELF inflammatory cells decreased after GSH therapy. This paralleled observations that GSH added in vitro to CF ELF inflammatory cells suppressed O2. release. No adverse effects were noted during treatment. Together, these observations demonstrate the feasibility of using GSH aerosol to restore RES oxidant-antioxidant balance in CF, and support the rationale for further clinical evaluation.

Systemic deficiency of glutathione in cystic fibrosis
Roum JH, Buhl R, McElvaney NG, Borok Z, Crystal RG. [J Appl Physiol 1993 Dec;75(6):2419-24] One process contributing to the airway derangement is the chronic burden of oxidants released by inflammatory cells on the respiratory epithelial surface. With this background, we hypothesized that glutathione in respiratory epithelial lining fluid (ELF) in CF patients might be oxidized and/or diminished in amount compared with that in normal subjects. As predicted, ELF in CF patients was characterized by a deficiency of glutathione, but this was secondary to a reduction in reduced glutathione. Unexpectedly, there was also a marked deficiency of reduced glutathione in plasma; i.e., the glutathione "deficiency" observed in ELF in CF patients is not limited to the site of the inflammation but is systemic. Although the etiology of this generalized deficiency of extracellular glutathione is unknown, it is important in considering options for treating the concomitant and devastating lung pathology in this disorder.

Lymphocyte glutathione levels in children with cystic fibrosis
Lands LC, Grey V, Smountas AA, Kramer VG, McKenna D. [Chest 1999 Jul;116(1):201-5] Lung disease in cystic fibrosis (CF) is characterized by a neutrophilic inflammatory response. This can lead to the production of oxidants, and to oxidative stress in the lungs. Glutathione (GSH) represents the primary intracellular antioxidant, and provides an important defense in the epithelial lining fluid.... lymphocyte GSH reflects lung GSH concentrations, .....the inverse correlation between lymphocyte GSH concentration and lung function as a reflection of upregulation of GSH production by lung epithelial tissue in response to oxidative stress ....correlation between lymphocyte GSH concentration and nutritional status as a reflection of the role of cysteine in hepatic glutamine metabolism....the increased demand for GSH production in the face of ongoing inflammation suggests a potential role for supplementation with cysteine donors.

Erythrocytic glutathione in cystic fibrosis. A possible marker of pulmonary dysfunction
Mangione S, Patel DD, Levin BR, Fiel SB. [Chest 1994 May;105(5):1470-3] We chose patients with CF because this disease is characterized by severe bronchial inflammation and marked oxidant-antioxidant imbalance. Although the GSH concentration of the two study groups was not significantly different, the RBC GSH concentration of patients with CF had a greater variability and was also inversely and significantly correlated to tests of pulmonary function. These data indicate a large and significant interindividual variability of erythrocytic antioxidants in patients with CF, with a compensatory, but probably inadequate, increase in patients with more severe respiratory deterioration. Red blood cell GSH concentration may thus provide a biologic marker for disease severity and a rationale for antioxidant manipulation in these patients.

Oxidative stress and regulation of glutathione in lung inflammation
Rahman I, MacNee W. [Eur Respir J. 2000 Sep;16(3):534-54.]
Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra- and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro-inflammatory processes in the lungs. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant gamma-GCS and pro-inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. This review describes the redox control and involvement of nuclear factor-kappaB and activator protein-1 in the regulation of cellular glutathione and gamma-glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant-mediated susceptibility/tolerance, gamma-glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

Treatment of obstructive airway disease with a cysteine donor protein supplement: a case report
Lothian B, Grey V, Kimoff RJ, Lands LC. Department of Pediatrics, McGill University Health Centre-Montreal Children's Hospital, Montreal, Quebec, Canada.[Chest 2000 Mar;117(3):914-6] Case Study of a patient with Chronic Obstructive Pulmonary Disorder (COPD) - Oxidant/ antioxidant imbalance can occur in obstructive airways disease as a result of ongoing inflammation. Glutathione (GSH) plays a major role in pulmonary antioxidant protection. As an alternative or complement to anti-inflammatory therapy, augmenting antioxidant protection could diminish the effects of inflammation. We describe a case of a patient who had obstructive lung disease responsive to corticosteroids, and low whole blood GSH levels. After 1 month of supplementation with a whey-based oral supplement designed to provide GSH precursors, whole blood GSH levels and pulmonary function increased significantly and dramatically. The potential for such supplementation in pulmonary inflammatory conditions deserves further study.

Evidence of a defective thiol status of alveolar macrophages from COPD patients and smokers. Chronic obstructive pulmonary disease
Tager M, Piecyk A, Kohnlein T, Thiel U, Ansorge S, Welte T. [Free Radic Biol Med 2000 Dec;29(11):1160-5] In increasing numbers of pulmonary diseases an association with a loss of intracellular thiols, mainly glutathione, is postulated. Therefore, the quantitative measurement of thiols within different viable cells is a possible metabolic parameter for cellular function and defense capacity of all pulmonary immune cells including alveolar macrophages (AM), that are highly compromised by oxidative stress. AM obtained from bronchoalveolar lavage (BAL) of smokers and patients with chronic obstructive pulmonary disease (COPD) showed a significant thiol deficiency compared to a nonsmoker/non-COPD group. Lowest thiol concentrations (47% of control) were detected within the smoker(+)/COPD(+) group. This intracellular thiol deficiency significantly correlated with reduced lung function. With regard to the tightly regulated thiol metabolism of immune cells, these results imply the onset of functional disturbances in thiol deficient AM.

Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema
Engelen MP, Schols AM, and others. [Am J Respir Crit Care Med 2000 Jan;161(1):98-103.] "Chronic obstructive pulmonary disease (COPD) is often characterized by an impaired skeletal muscle energy metabolism, which is at least partly related to chronic hypoxia and a reduced diffusing capacity. This study illustrates that reduced glutamate levels in skeletal muscle of patients with emphysema are possibly related to an enhanced glycolytic activity and associated with decreased glutathione levels."

Frequent paracetamol use and asthma in adults
Shaheen SO, Sterne JA, Songhurst CE, Burney PG. [Thorax 2000 Apr;55(4):266-70] BACKGROUND: The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma....RESULTS: Paracetamol use was positively associated with asthma...amongst cases increasing paracetamol use was associated with more severe disease. Frequent paracetamol use was positively associated with rhinitis, but aspirin use was not. CONCLUSIONS: Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults.

Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart- lung transplantation
Behr J, Maier K and others. [Transplantation 2000 May 15;69(9):1856-60.] "Reduced glutathione was positively correlated with forced expiratory volume... We conclude that excessive oxidative stress and a lack of glutathione are associated with BOS after H/LTX and may play relevant roles in the development of this disorder."

The effects of chronic alcohol abuse on pulmonary glutathione homeostatis
Moss M, Guidot DM, and others. [Am J Respir Crit Care Med 2000 Feb;161(2 Pt 1):414-9.] "This is the first report that chronic alcohol abuse alters glutathione homeostasis in the human lung, and suggests a potential mechanism by which chronic alcohol abuse predisposes susceptible patients to develop ARDS (acute respiratory distress syndrome). Recently, we determined that chronic ethanol ingestion in rats decreased the alveolar epithelial lining fluid (ELF) concentration of the antioxidant glutathione (GSH), which is a characteristic finding in patients with ARDS. However, the effects of chronic alcohol abuse on the human alveolar epithelium are essentially unknown.

Characterization of N-acetylcysteine and ambroxol in antioxidant therapy
Gillissen A and Nowak D. [Respir Med 1998 Apr;92(4):609-23.] "This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol." Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach.

Does N-acetyl-L-cysteine influence cytokine response during early human septic shock?
Spapen H, Zhang HB, and others. [Chest 1998 Jun;113(6):1616-24.] In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.

GSH: Allergies and Lung Protection

The risk of developing respiratory allergies from exposure to diesel emissions depends largely on genetics, according to a study funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

Researchers from the Keck School of Medicine of the University of Southern California and the David Geffen School of Medicine at UCLA have found that genetic characteristics seen in about half the population leave allergy-sufferers particularly susceptible to the effects of diesel particles.

Here are the relevant findings from the study:

People with a certain genetic makeup are more susceptible to allergies caused by diesel engine exhaust.

Antioxidants can detoxify these particles and temper the body's allergic inflammatory response. The better the body can use antioxidants to defend itself, the better it may protect itself from airborne pollutants.

The enzymes glutathione S-transferase M1, or GSTM1, and glutathione S-transferase P1, or GSTP1 - that metabolize reactive oxygen species and detoxify chemicals present in diesel exhaust - were studied for their role in protecting the lungs.

GSTM1 occurs in two common forms in the population-either "present" or "null." People born with two of the null form of the gene cannot produce the GSTM1 protective enzyme at all.

The GSTP1 gene can occur with a common variation called ile105. People born with two of the ile105 form of the gene produce a less-effective form of the GSTP1 enzyme.

People who lack the GSTM1 enzyme exhibit a larger allergic response than others. Also, those who lack GSTM1 and have at least one GSTP1 ile105 genetic variant show an even larger allergic response to diesel exhaust particles.

The findings suggest that people who lack the genes to make key antioxidants may have difficulty fighting the harmful effects of air pollution.

Up to 50 percent of the United States population could be in jeopardy of experiencing health problems related to air pollution because of these genetic variations.

Overcoming this genetic deficiency could possibly be accomplished by either giving people drugs that replace the role of the genes or by boosting the body's natural defenses.

Antioxidants may prevent the effects that air pollution have on allergic inflammation.

The research suggest that boosting levels of antioxidants like glutathione, may prevent the effects that air pollution have on allergic inflammation.

The Original Article from the Lancet:
Effect of glutathione-S- transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study
F Gilliland et al. [The Lancet; 363 (9403): 119-25 (2004)]

Clin Exp Allergy. 1996 Jul;26(7):838-47

Reduced platelet glutathione peroxidase activity and serum selenium concentration in atopic asthmatic patients.

Misso NL, Powers KA, Gillon RL, Stewart GA, Thompson PJ.

Department of Medicine, University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Australia.

BACKGROUND: Asthmatic inflammation results in increased oxygen free radical generation and assessment of the activity of the selenium (Se) dependent anti-oxidant enzyme, glutathione peroxidase (GSH-Px) in asthma may therefore be important. 

OBJECTIVE: To test the hypothesis that reduced GSH-Px activity and Se intake contribute to asthmatic inflammation, platelet and whole blood GSH-Px activities and serum and whole blood Se concentrations were measured and compared in atopic and non-atopic asthmatic patients and non-asthmatic control subjects. 

METHODS: GSH-Px activities of whole blood and isolated platelets were assessed in 41 asthmatic patients (33 atopic) and 41 age- and sex-matched non-asthmatic subjects (15 atopic) by spectrophotometric assay based on the oxidation of NADPH. Se concentrations were determined by semi-automated fluorimetric assay. 

RESULTS: Mean (+/-SD) platelet GSH-Px activity was lower in asthmatic (89.5 +/- 45.7 mumol NADPH oxidized min-1 g-1 of protein) than in non-asthmatic subjects (109.9 +/- 41.9; P = 0.038) and in atopic (89.7 +/- 45.1, n = 48) compared with non-atopic subjects (113.7 +/- 40.9, n = 34; P = 0.016). Mean whole blood GSH-Px activity was also lower in atopic (12.2 +/- 5.2 mumol NADPH oxidized min-1 g-1 of Hb) than in non-atopic subjects (14.5 +/- 4.2; P = 0.038). In non-asthmatic subjects, the mean whole blood GSH-Px activity was lower in men (9.9 +/- 3.5) than in women (14.5 +/- 3.7; P = 0.0004) and was positively correlated with age (r = 0.51; P = 0.0006). Mean serum Se was lower in asthmatic (1.07 +/- 0.12 mumol/L) than in non-asthmatic subjects (1.16 +/- 0.31; P = 0.036). Using multiple linear regression, asthma was an independent predictor of decreased platelet GSH-Px after gender, age and serum Se were taken into account (P = 0.048) while atopy was a significant predictor of low whole blood GSH-Px independent of asthma, gender, age and whole blood Se (P = 0.033). 

CONCLUSIONS: In addition to Se status, atopy, gender and age all appear to influence GSH-Px activity, although the relative importance of these factors may differ in asthmatic and non-asthmatic populations. It seems likely that the reduced activity of this enzyme in platelets and blood may reflect mechanisms associated with the pathogenesis and severity of asthma.

PMID: 8842559 [PubMed - indexed for MEDLINE]

Clin Chim Acta. 2001 Mar;305(1-2):107-14.

Excessive free radical generation in the blood of children suffering from asthma.
Shanmugasundaram KR, Kumar SS, Rajajee S.

Department of Medical Biochemistry, Dr. A.L.M.P.G. Institute of Basic Medical Sciences, University of Madras, Taramani Campus, - 600 113, Chennai, India. erbs@satyam.net.in

The aim of the present study is to evaluate the biochemical parameters in blood relevant to oxygen free radicals and antioxidant defenses in children with asthma. A total of 210 asthmatic children, aged 5-18 years, were studied at two different times, once during a severe episode of wheeze (during episode category) and the other after recovery (resting condition). A total of 180 healthy children participated in the study as age and sex matched healthy controls. Superoxide and hydroxyl radical assays were used as a measure of free radical formation. Antioxidant enzymes and free radical scavengers in blood were also assayed. Lipid peroxidation products were assayed in plasma and erythrocytes to evaluate the imbalance (if any) between oxidant (radical) formation and their inactivation. Serum IgE concentrations and peak expiratory flow rate (PEFR) were used as measures of allergic reactions and residual lung capacity, respectively. Excessive production of superoxide and hydroxyl radicals were noted in the blood cells in asthmatics and were correlated to the severity of disease measured as PEFR. Superoxide dismutase and free radical scavengers in blood were significantly lower in asthma, even during resting condition. The present observations endorse the correlation between disease severity and oxygen radical production in asthma subjects. Oxygen metabolites may play a direct or indirect role in the modulation of airway inflammation. Excessive superoxide and hydroxyl radical production may be used as a marker for susceptibility to asthma and for monitoring therapeutic measures.

PMID: 11249929 [PubMed - indexed for MEDLINE]

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Autism Linked to Overactive Immune System, Study Finds

By ANDRÉ PICARD
PUBLIC HEALTH REPORTER
Tuesday, November 16, 2004 - Page A17 Autism, a mysterious and increasingly common disorder, may be caused, at least in part, by a malfunction in the immune system, a new study suggests.

Researchers studying the brains of people with autism say they have found strong evidence that parts of the immune system were overactive, causing chronic inflammation. This inflammation appears to cause damage to the brain in a manner similar to what is seen in other neurodegenerative conditions such as Alzheimer's disease, Parkinson's and Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease). Autism is a brain disorder that appears in early childhood. The cause, or causes, are unknown, though immune reactions have long been suspected as playing a role.

"These findings reinforce the theory that immune activation in the brain is involved in autism," said Dr. Carlos Pardo Villamizar, a neuroimmunologist at Johns Hopkins University School of Medicine in Baltimore, Md.

There are a number of theories about what triggers the damaging inflammation, including birth trauma, exposure to toxins, childhood vaccines, diet and viruses.

The new research throws cold water on a number of these notions, suggesting strongly that immune system problems begin in the womb -- likely in the second trimester when the nervous system is developing -- and continue throughout life.

The study, published in today's edition of the Annals of Neurology, was conducted using the brain tissue of 11 people with autism, aged 5 to 44, who died from accidents or injuries. The victims' brains were donated to a large U.S. autism tissue program that promotes research.

Researchers measured a number of immune-system proteins called cytokines and chemokines, and found abnormal patterns that suggested chronic inflammation. These measures were compared to those conducted on non-autistic victims who died in similar circumstances, which showed no such inflammation.>

"The pattern of cellular and protein findings indicated that they are part of the innate immune system and do not appear to be caused by immune abnormalities outside the brain," Dr. Pardo said.

The article below indicates that in cases of autism, glutathione synthesis may be impaired.   As you will read in the following study, glutathione plays a crucial role as a neuro protectant and facilitates neuro transmission.  As such replenishing glutathione stores in this case may be beneficial.

Prostaglandins Leukot Essent Fatty Acids. 2002 Nov;67(5):341-3.

Investigation of antioxidant enzymes in children with autistic disorder.

Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T.

GATA Child and Adolescent Psychiatry Department, Etlik, Ankara, Turkey

Impaired antioxidant mechanisms are unable to inactivate free radicals that may induce a number of pathophysiological processes and result in cell injury.

Thus, any abnormality in antioxidant defence systems could affect neurodevelopmental processes and could have an important role in the etiology of autistic disorder.

The plasma levels of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), and erythrocyte levels of GSH-Px were investigated in 45 autistic children and compared with 41 normal controls. Levels of erythrocyte SOD, erythrocyte and plasma GSH-Px were assayed spectrophotometrically.  

Activities of erythrocyte SOD, erythrocyte and plasma GSH-Px in autistic children were significantly lower than normal. \  These results indicate that autistic children have low levels of activity of blood antioxidant enzyme systems; if similar abnormalities are present in brain, free radical accumulation could damage brain tissue.

PMID: 12445495 [PubMed - in process]

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Cancer

Glutathione plays a role in eliminating many carcinogens and also maintains an optimized immune function, providing stronger anti-tumour defences. Cancer Letters 57:91-94, 1991

High Cysteine Levels Linked to Lower Rates of Breast Cancer 15 July, 2003; A Prospective Study of Plasma Cysteine and Risk of Breast Cancer. Abstract LB-3
High serum levels of cysteine are linked to a lower risk of breast cancer, according to a presentation at the 94th Annual Meeting of the American Association for Cancer Research (AACR). Women in the group with the highest levels of plasma cysteine had a 56% reduction in the risk of developing breast cancer. These findings suggest that boosting of plasma cysteine levels might have a preventative effect on breast cancer. Cysteine itself appears to be neurotoxic, and researchers in this field have instead looked to the precursors of cysteine for therapeutic use. Preclinical studies previously suggested that cysteine precursors have an anticarcinogenic effect. Whey protein is naturally high in cystine (the disulfide form of the amino acid cysteine) and contains significantly more than many other sources of protein. The protective effect of high cysteine levels appeared to be strongest in women with body mass index levels below 25 and in premenopausal women.


Whey protein, glutathione protect against prostate cancer

28 May, 2003; Ohio State University [Kent, Harper, and Bomser; Toxicology In Vitro, February, 2003, 17(1):27-33]
New research suggests that whey, a liquid by-product from cheese production, may play a role in helping prevent prostate cancer. Antioxidants such as glutathione have been shown to control cancer-causing free radicals. Cancer researchers suspect that the accumulation of free radicals plays a role in the development of prostate cancer. In the current study, the Ohio State scientists found that treating prostate cells with whey protein elevated glutathione levels in the cells by up to 64 percent. Whey contains the amino acid cysteine - a key ingredient for making glutathione in the body. Cysteine is the amino acid that helps create healthy glutathione levels in the prostate, and glutathione helps keep free radicals under control. "In diseases like cancer, there's usually a reduction in the body's overall capacity to deal with oxidative stress," he continued. The researchers warn that simply eating cheese won't ensure an increase in glutathione levels, because cysteine is contained in the whey that's separated from cheese early in the cheese-making process. 

The Glutathione Antioxidant System Anticancer Research Journal 23: 1411-1416 (2003)  Bounous G, Molson JH
The glutathione antioxidant system is the principal protecting mechanism of the cell and is a crucial factor in the development of the immune response by the immune cells.  Experimental data demonstrates that a cysteine-rich whey protein concentrate represents and effective cysteine delivery system for glutathione replenishment during the immune response.  Animal experiments showed that the concentrates of whey protein also exhibit anti-cancer activity. For more information, please read The Antioxidant System .

Enchancing effect of patented whey protein isolate on cytotoxicity of an anticancer drug
Tsai WY, Chang WH, Chen CH, Lu FJ. [Nutr Cancer. 2000;38(2):200-8.] To determine the enhancing effect of a whey protein isolate on the cytotoxicity of a potential anticancer drug, baicalein, the human hepatoma cell line Hep G2 was assigned to grow in different media for four days, and cell growth and apoptosis were investigated.....survival rate was significantly lower in cells grown in baicalein + un-denatured whey protein than in cells grown in baicalein alone.....In conclusion, undenatured whey protein seemed to enhance the cytotoxicity of baicalein by inducing more apoptosis... This is the first study to demonstrate, in vitro, that undenatured whey protein may function as an adjuvant in cancer treatments.

Nutriceutical Modulation Of Glutathione With A Humanized Native Milk Serum Protein Isolate: Application In AIDS And Cancer - Go  for order info
S. Baruchel, G. Viau, R. Olivier, G. Bounous, M.A. Wainberg [Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases V Luc Montagnier et al., (Ed.) Marcel Dekker Inc., New York: 447-461, 1998 . ABSTRACT V] The biological activity of the proteins isolated from cow's milk in un-denatured whey protein depends on the preservation of those labile proteins which share with the predominant human milk proteins the same extremely rare glutathione (GSH)-promoting components. In a pilot study, this type of whey protein concentrate was found to be well tolerated in children with AIDS and wasting syndrome and was found associated with an improvement of the nutritional status of the patient.
Whey proteins in cancer prevention
Bounous G, Batist G, Gold P. [Cancer Lett. 1991 May 1;57(2):91-4. Review.] Epidemiological and experimental studies suggest that dietary milk products may exert an inhibitory effect on the development of several types of tumors......the antitumor activity of the dairy products is in the protein fraction and more specifically in the whey protein component of milk......Whey protein is particularly rich in substrates for GSH synthesis. We suggest that whey protein may be exerting its effect on carcinogenesis by enhancing GSH concentration.

Whey protein concentrate (WPC) and glutathione modulation in cancer treatment
Bounous G. [Anticancer Res. 2000 Nov-Dec;20(6C):4785-92. Review.] Whey protein concentrate has been shown to represent an effective and safe cysteine donor for GSH replenishment during GSH depletion in immune deficiency states........the concentrates of whey proteins also exhibit anti-carcinogenesis and anticancer activity........and may have anti-tumor effect on low volume of tumor via stimulation of immunity through the GSH pathway......Case reports.....strongly suggest an anti-tumor effect of a whey protein dietary supplement in some urogenital cancers. This non toxic dietary intervention, which is not based on the principles of current cancer chemotherapy, will hopefully attract the attention of laboratory and clinical oncologists.

In vitro selective modulation of cellular glutathione by a humanized native milk protein isolate in normal cells and rat mammary carcinoma model
Baruchel S, Viau G. [Anticancer Res. 1996 May-Jun;16(3A):1095-9.] We report the in vitro selective inhibitory activity of a humanized whey protein concentrate on growth of mammary carcinoma cells and Jurkat T cells in comparison to normal peripheral blood mononuclear cells. We relate this inhibitory activity to a selective depletion of intracellular glutathione synthesis. The use of humanized whey protein concentrate as a food supplementation may have direct implication in clinical trial with adjuvant chemotherapy.

Effect of adding glutathione (GSH) to cisplatin (CDDP) in the treatment of stage I-IV ovarian cancer:
(Meeting abstract). Bowman A; Perren T; Wilkinson P; Prescott RJ; Quinn KJ; Tedeschi M; Smyth [JF Address: ICRF Medical Oncology Unit, Edinburgh, UK Source: Br J Cancer 1994;71(Suppl 24):14] Abstract: Previous studies have suggested that glutathione (GSH) can reduce the toxicities of cisplatin (CDDP) chemotherapy. In a double-blind phase III study conducted at 9 British oncology centers... GSH reduced depression and significantly improved 8 other symptoms including emesis and peripheral neurotoxicity. Thus, the addition of GSH to CDDP allows more cycles of CDDP to be administered; quality of life is improved and response rates may be enhanced.

The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study
Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD. [Anticancer Res. 1995 Nov-Dec;15(6B):2643-9.] Glutathione (GSH) concentration is high in most tumour cells and this may be an important factor in resistance to chemotherapy.........experiments have shown a differential response of tumour versus normal cells to various cysteine delivery systems.........at concentrations that induce GSH synthesis in normal human cells, a specially prepared whey protein concentrate caused GSH depletion and inhibition of proliferation in human breast cancer cells. On the basis of this information five patients with metastatic carcinoma of the breast, one of the pancreas and one of the liver were fed 30 grams of this whey protein concentrate daily for six months.......The results indicate that whey protein concentrate might deplete tumour cells of GSH and render them more vulnerable to chemotherapy.

Dietary whey protein inhibits the development of dimethylhydrazine induced malignancy
Bounous G, Papenburg R, Kongshavn PA, Gold P, Fleiszer D. [Clin Invest Med. 1988 Jun;11(3):213-7.] In conclusion, a whey protein diet appears to significantly inhibit the incidence and growth of chemically induced colon tumors in mice.

Dairy proteins protect against dimethylhydrazine-induced intestinal cancers in rats
McIntosh GH, Regester GO, Le Leu RK, Royle PJ, Smithers GW. [J Nutr. 1995 Apr;125(4):809-16.] Whey and casein diets were more protective against the development of intestinal tumors than were the red meat or soybean diets......Intracellular concentration of glutathione, an antioxidant and anticarcinogenic tripeptide, measured in liver, was greatest in whey protein- and casein-fed rats and lowest in soybean-fed animals.....Whatever the mechanism(s), dairy proteins, and whey proteins in particular, offer considerable protection to the host against dimethylhydrazine-induced tumors relative to the other protein sources examined.

Effect of whey protein isolate on intracellular glutathione and oxidant-induced cell death in human prostate epithelial cells
Kent KD, Harper WJ, Bomser JA. [Toxicol In Vitro. 2003 Feb;17(1):27-33.] The objective of this study was to determine whether enzymatically hydrolyzed whey protein isolate (WPI) could increase intracellular GSH concentrations and protect against oxidant-induced cell death in a human prostate epithelial cell line (designated RWPE-1). Treatment of RWPE-1 cells with hydrolyzed WPI significantly increased intracellular GSH by 64%, compared with control cells receiving no hydrolyzed WPI. A similar increase in GSH was observed with N-acetylcysteine, a cysteine-donating compound known to elevate intracellular GSH. Hydrolyzed WPI significantly protected RWPE-1 cells from oxidant-induced cell death, compared with controls receiving no WPI. The results of this study indicate that WPI can increase GSH synthesis and protect against oxidant-induced cell death in human prostate cells.

Whey protein isolate increases glutathione levels in human prostate epithelial cells
K. D. Kent, J. A. Bomser, and W. J. Harper. [Annual Meeting and Food Expo - Anaheim, California, Session 73, Dairy Foods: Probiotics and bioactive components in milk] Prostate cancer is the second leading cause of cancer death among American men. Studies suggest that dietary whey proteins may reduce the risk for cancer by increasing cellular levels of the antioxidant glutathione. Whey proteins are rich in cysteine, the hypothesized rate-limiting amino acid for glutathione synthesis. Supplementation with whey protein isolate may represent a means to increase glutathione synthesis within the prostate. The objective of this study was to determine the effect of whey protein isolate supplementation on glutathione levels in human prostate epithelial cells (RWPE-1).... an increase in available cysteine is responsible for the elevation of glutathione within the prostate epithelial cells.... hydrolyzed whey protein isolate can significantly increase glutathione levels within the prostate epithelium. This represents a potential mechanism by which whey protein isolate can provide protection against the development of prostate cancer.

Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells
Schnelldorfer T, Gansauge S, Gansauge F, Schlosser S, Beger HG, Nussler AK. [Cancer. 2000 Oct 1;89(7):1440-7.] Recent studies have demonstrated that various tumors express enhanced levels of the radical scavenger glutathione (GSH). Moreover, there are grounds for claiming that GSH plays a crucial role in cell proliferation and tumor resistance. In the current study, we investigated the relation between cell growth and GSH levels in the pancreatic adenocarcinoma cell line, AsPC-1, and the significance of GSH in tumor resistance to chemotherapy. Analysis of GSH in pancreatic tissues demonstrated increased GSH levels in cancerous compared with normal tissue. Our results show enhanced GSH levels in pancreatic carcinoma and an essential role of GSH in cell proliferation and in resistance of AsPC-1 cells. Therefore, GSH-depletion may improve the efficacy of adjuvant therapy in pancreatic carcinoma.

Milk and dairy products in cancer prevention: focus on bovine lactoferrin
Tsuda H, Sekine K, Ushida Y, Kuhara T, Takasuka N, Iigo M, Han BS, Moore MA. [Mutat Res 2000 Apr;462(2-3):227-33] Whey protein may also be beneficial, as shown by both animal and human studies, and experimental data have demonstrated that the major component bovine lactoferrin (bLF), inhibits colon carcinogenesis in the post-initiation stage in male F344 rats treated with azoxymethane (AOM) without any overt toxicity.... bLF might find application as a natural ingredient of milk with potential for chemoprevention of colon and other cancers.

Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies
Tsuda H, Sekine K, Fujita K, Ligo M. [Biochem Cell Biol. 2002;80(1):131-6.] In experimental studies, bovine lactoferrin (bLF) has been found to significantly inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Furthermore, concomitant administration with carcinogens resulted in inhibition of colon carcinogenesis.. Anti-metastatic effects were moreover detected when bLF was given intragastrically to mice bearing highly metastatic colon carcinoma 26 cells (Co 26Lu), with apparent enhancing influence on local and systemic immunity. Marked increase in the number of cytotoxic T and NK cells in the mucosal layer of the small intestine and peripheral blood cells was thus found, this in turn enhancing the production of Interleukin 18 (IL-18) and caspase-1 in the epithelial cells of the small intestine, with possible consequent induction of interferon (IFN)-gamma positive cells. Furthermore, bLF has been found to exert anti-hepatitis C virus (HCV) activity in a preliminary clinical trial in patients with chronic active hepatitis due to this virus, a main causative factor in hepatocellular carcinoma development in Japanese. More extensive clinical trials are now underway in the National Cancer Center Hospital and other institutes to further explore the preventive potential against colon carcinogenesis.

Prevention of colon carcinogenesis and carcinoma metastasis by orally administered bovine lactoferrin in animals
Tsuda H, Sekine K, Takasuka N, Toriyama-Baba H, Iigo M. [Biofactors 2000;12(1-4):83-8] Bovine lactoferrin (bLF), a milk protein known to have bacteriostatic properties was examined for its preventive effects on colon and other organ carcinogenesis and experimental metastasis. .. Results of those experiments indicate that bLF remarkably prevents colon carcinogenesis and lung metastasis of colon carcinoma cells, possibly due to increasing cytotoxic cells in the peripheral blood.

Modulation of glutathione by a cysteine pro-drug enhances in vivo tumor response
Wang T, Chen X, Schecter RL, Baruchel S, Alaoui-Jamali M, Melnychuk D, Batist G. [J Pharmacol Exp Ther 1996 Mar;276(3):1169-73] Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular glutathione increases toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation using the drug buthionine sulfoximine.... some drug-resistant cell lines have increased GSH levels, ... enhancing glutathione concentrations in animal tissues protects against a variety of xenobiotic agents, suggests a different potential approach to improve anticancer therapy. This report describes evidence that OTZ provides this effect in an in vivo rat mammary tumor model... the lack of increased GSH in tumor in response to OTZ.

Glutathione based approaches to improving cancer treatment
Kauvar LM, Morgan AS, Sanderson PE, Henner WD. [Chem Biol Interact. 1998 Apr 24;111-112:225-38.]
The use of cytotoxic chemotherapy for cancer therapy has been very successful in the treatment and often cure of patients with particular neoplasms, such as testicular carcinomas and some lymphomas. In addition, the use of adjuvant chemotherapy in patients whose primary tumor has been surgically removed contributes significantly to cure rates in some of the more common malignancies such as breast carcinoma and colon cancer. Nonetheless, for most patients with metastatic malignancies, current antineoplastic drugs provide only brief remissions with few or no long term cures. In addition, the side effects of therapy lead to substantial morbidity in nearly all patients. Insights derived from model system studies on two glutathione based lead compounds, TER286 and TER199, suggest new clinical strategies and raise interesting basic research questions regarding the cell biology foundations of cancer chemotherapy.

Selective modulation of glutathione levels in human normal versus tumor cells and subsequent differential response to chemotherapy drugs
Russo A., Degraff W., Friedman N., Mitchell EB. [Cancer Res. 26: 2845-48,1986.] Cellular glutathione (GSH) levels were found to be 7-fold higher in a human lung adenocarcinoma cell line (A549) than in a normal human lung fibroblast line (CCL-210). These studies demonstrate that selective differential chemotherapy responses of normal versus tumor cells is possible by manipulating the GSH synthetic cycle.... such manipulation in GSH levels might yield a therapeutic gain for carefully selected chemotherapy drugs.

Glutathione and glutathione-dependent enzymes in cancer drug resistance
McLellan LI, Wolf CR. [Drug Resist Updat 1999 Jun;2(3):153-164] Glutathione and glutathione-dependent enzymes play a central role in cellular defence against toxic environmental agents. Modulation of cellular glutathione homeostasis can also have a profound effect on the sensitivity of cancer cells to a wide range of drugs used in chemotherapy. New data demonstrating the importance of these pathways in cytoprotection and greater understanding of the mechanisms which regulate their function reveal a number of new targets for novel anti-cancer agents.

Glutathione level and its relation to radiation therapy in patients with cancer of uterine cervix
Mukundan H, Bahadur AK, Kumar A, Sardana S, Naik SL, Ray A, Sharma BK.[Indian J Exp Biol. 1999 Sep;37(9):859-64.] The study was aimed to determine plasma glutathione as well as erythrocyte glutathione and glutathione peroxidase in patients with invasive cervical carcinoma before initiation and after completion of radiotherapy and subsequently, at the time of first three monthly follow-up visit. The levels of plasma glutathione, erythrocyte glutathione and glutathione peroxidase activity were found to be lower in all cervical cancer patients as compared to age matched normal control women. The study indicates a change in antioxidant status in relation with the glutathione system among patients with invasive carcinoma of the uterine cervix. This study also demonstrates the effect of radiation therapy on this antioxidant system.

Role of cysteine and glutathione in HIV infection and cancer cachexia: therapeutic intervention with N-acetylcysteine
Droge W. et al. [Adv Pharm 38: 581-600, 1997.] No abstract available.

Glutathione and lipid peroxidation levels in human breast tumors
Coban T, Mabsout A, Eke BC, Bulbul D, Berberoglu U, Iscan M. [Neoplasma. 1998;45(3):151-6.] The levels of reduced glutathione (GSH) and lipid peroxidation (LP) of breast tumor and surrounding tumor free (normal) tissues of 39 breast cancer female patients with infiltrating ductal carcinoma and the relationship between these two parameters were investigated. Large interindividual variations in the levels of GSH and LP were found in both tumor and normal tissues. The mean GSH levels of tumors were significantly higher than those of normal tissues. This tendency did not change with the stage and grade (excluding grade 1) of the malignancy, menopausal status and chemotherapy treatment. These results reveal that the GSH, but not LP, could be a marker of breast malignancy and that the increase in GSH level is not sufficient to lower the LP level in human breast tumors.

N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyp
Estensen RD, Levy M, and others. [Cancer Lett 1999 Dec 1;147(1-2):109-14.] "This investigation is part of an effort to develop chemoprevention for carcinogenesis of the large bowel. The agent investigated is N-acetylcysteine (NAC). Patients with previous adenomatous colonic polyps are a cohort with increased risk for colon cancer and an increased PI of colonic crypts. Since this decrease in proliferative index may be an indicator of decreased risk of colon cancer, more extensive studies of the potential of NAC as a chemopreventive agent for colon cancer appear warranted."

Colon cancer: dietary modifications required for a balanced protective diet
McIntosh GH. [Prev Med 1993 Sep;22(5):767-74] When comparing differing protein sources, whey protein concentrate was found to be very protective relative to red meat and other protein sources. Protein sources such as whey protein concentrate, insoluble dietary fiber from barley grain, and high calcium intake seem to be very promising. They may provide greater potential than attempts to lower the fat in the human diet.

The role of the thiol N-acetylcysteine in the prevention of tumor invasion and angiogenesis
Morini M, Cai T, Aluigi MG, Noonan DM, Masiello L, De Flora S, D'Agostini F, Albini A, Fassina G. [Int J Biol Markers. 1999 Oct-Dec;14(4):268-71. Review.] We have extensively studied the effects of N-acetylcysteine (NAC), a cytoprotective drug that can prevent in vivo carcinogenesis. Here we review our findings NAC completely inhibits gelatinolytic activity of metalloproteases and chemotactic and invasive activities of tumor cells. In addition, NAC reduces the number of lung metastases when malignant murine melanoma cells are injected into nude mice. NAC treatment decreases the weight of primary tumors and produces a dose-related increase in tumor latency. Moreover, oral administration of NAC reduces the formation of spontaneous metastases. In experimental metastasis assays, we have found a synergistic reduction in the number of lung metastases after treatment with doxorubicin (DOX) and NAC in nude mice. In tumorigenicity and spontaneous metastasis assays, the combined administration of DOX and oral NAC again has shown synergistic effects on the frequency and weight of primary tumors and local recurrences and completely prevented the formation of lung metastases. The addition of NAC to endothelial cells strongly reduces their invasive activity in response to angiogenic stimuli. Oral administration of NAC reduces the angiogenic response induced by KS tumor cell products, confirming the ability of NAC to inhibit the invasive activity of endothelial cells in vivo and thereby blocking angiogenesis.

Breast cancer: pretreatment drug resistance parameters (GSH-system, ATase, P-glycoprotein) in tumor tissue and their correlation with clinical and prognostic characteristics
Buser K, Joncourt F, Altermatt HJ, Bacchi M, Oberli A, Cerny T. [Ann Oncol. 1997 Apr;8(4):335-41.] The identification of new factors predicting relapse, outcome and response to systemic therapy in breast cancer is warranted. High levels of GSH, GST and GPx were associated with favorable clinical characteristics and good prognosis, whereas low levels of GSH and GST activity were associated with more aggressive or more advanced disease.

Antioxidant action via p53-mediated apoptosis
Liu M, Pelling JC, Ju J, Chu E, Brash DE. [Cancer Res. 1998 Apr 15;58(8):1723-9.] Sulfur-containing antioxidants such as N-acetylcysteine and dimercaptopropanol induced apoptosis in several transformed cell lines and transformed primary cultures but not in normal cells. In contrast, chain-breaking antioxidants such as vitamin E lacked this activity. An increased glutathione level was not required for apoptosis; however, all apoptosis-inducing antioxidants elevated the total cellular thiol levels. N-Acetylcysteine elevated p53 expression posttranscriptionally by increasing the rate of p53 mRNA translation rather than by altering the protein stability. Manipulating p53-dependent apoptosis with nontoxic antioxidants may have a direct clinical application.

1: Anticancer Res. 2004 Mar-Apr;24(2B):553-4.

Molecular pathogenesis and prevention of prostate cancer.

Bounous G, Beer D.

Research and Development Department, Immunotec Research Ltd., Vaudreuil-Dorion, Quebec, Canada. jmolson@immunotec.com

Studies in laboratory animals indicate inhibition of chemically-induced carcinoma by cystine-rich diets enhancing the cysteine-GSH antioxidant system. The progression of carcinoma of the prostate is also inhibited by these diets, which were later found to raise the level of GSH in the prostate epithelium of man. New data presented at the July 13, 2003 meeting of the American Association for Cancer Research indicates that higher levels of total cysteine in plasma may predict a reduced risk for breast cancer. This prospective investigation was conducted among 32,000 women in the Nurses Health study. The previously reported prostate cancer data appears then not to be strictly gender-related as the antioxidant role of the cysteine-GSH system may also apply to breast cancer prevention.

Publication Types:

Review
PMID: 15160993 [PubMed - indexed for MEDLINE]

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Digestive Diseases

Glutathione protects the body from the inflammation of gastritis, stomach ulcers, pancreatitis and inflammatory bowel disease including ulcerative colitis and Crohn's disease.

GSH and Digestive Disorders

Glutathione metabolism in Crohn's disease
Iantomasi T, Marraccini P, Favilli F, Vincenzini MT, Ferretti P, Tonelli F. [Biochem Med Metab Biol 1994 Dec;53(2):87-91] A statistically significant decrease of glutathione (GSH) and an increase of GSH disulfide (GSSG) both in healthy and ill ileum of patients with Crohn's disease in comparison with the controls (without this pathology) is demonstrated. However, the lowering of these levels was more remarkable in ill ileum in which high levels of GSSG were detected, too. These alterations may be in part explained by the changes obtained in GSH-related enzyme levels. Finally, considering the results that others and we obtained by studies on GSH oral absorption in rat intestine, an oral therapy of GSH in Crohn's disease is suggested.

Low levels of glutathione in endoscopic biopsies of patients with Crohn's colitis: the role of malnutrition
Miralles-Barrachina O, Savoye G, and others. [Clin Nutr 1999 Oct;18(5):313-7.] "Mucosal glutathione is markedly lower in active Crohn's colitis, even in healthy mucosa; glutathione depletion tends to be more severe in malnourished patients. Glutathione depletion may be related in part to malnutrition and contribute to a prolonged evolution of disease and could be a target for pharmacological and nutritional support." (Copyright 1999 Harcourt Publishers Ltd.)

Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease
Sido B, Hack V, and others. [Gut 1998 Apr;42(4):485-92.] " Decreased activity of key enzymes involved in GSH synthesis accompanied by a decreased availability of cyst(e)ine for GSH synthesis contribute to mucosal GSH deficiency in IBD. As the impaired mucosal antioxidative capacity may further promote oxidative damage, GSH deficiency might be a target for therapeutic intervention in IBD [inflammatory bowel disease].

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis
Esther Ardite, Miguel Sans, Juliá Panés, Francisco J. Romero, Josep M. Piqué, and José C. Fernández-Checa [Liver Unit (EA, JCF-C) and Department of Gastroenterology (MS, JP, JMP), Institut Malalties Digestives, Instituto Investigaciones Biomedicas August Pi I Suñer, Consejo Superior Investigaciones Cientificas, Barcelona, Spain; and Experimental Toxicology and Neurotoxicology Unit (FJR), Department of Physiology, School of Medicine and Dentistry, University of Valencia, Valencia, Spain] Because reactive oxygen species (ROS) have been implicated as mediators of inflammatory bowel disease (IBD), the purpose of the present work was to determine the functional role of mucosal GSH in the trinitrobenzenesulfonic acid in 50% ethanol (TNBS+ethanol)-induced colitis in rats. Accordingly, in vivo administration of NAC attenuates the acute colitis through increased mucosal GSH levels, suggesting that GSH precursors may be of relevance in the acute relapse of IBD.

Glutathione and Malnutrition

In vivo rates of erythrocyte glutathione synthesis in children with severe protein-energy malnutrition
Reid M, Badaloo A, and others. [Am J Physiol Endocrinol Metab 2000 Mar;278(3):E405-12.] "Children with edematous PEM had significantly lower erythrocyte GSH and slower absolute rates of GSH synthesis than children with nonedematous PEM ......These results confirm that GSH deficiency is characteristic of edematous PEM [protein-energy malnutrition] and suggest that this is due to a reduced rate of synthesis secondary to a shortage in cysteine."

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Chronic Fatigue Syndrome

Logan AC, Wong C.

CFS/FM Integrative Care Centre, Toronto, ON, Canada. Chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems. The etiology of CFS remains unclear; however, a number of recent studies have shown oxidative stress may be involved in its pathogenesis. The role of oxidative stress in CFS is an important area for current and future research as it suggests the use of antioxidants in the management of CFS. Specifically, the dietary supplements glutathione, N-acetylcysteine, alpha-lipoic acid, oligomeric proanthocyanidins, Ginkgo biloba, and Vaccinium myrtillus (bilberry) may be beneficial. In addition, research on food intolerance is discussed, since food intolerance may be involved in CFS symptom presentation and in oxidation via cytokine induction. Finally, recent evidence suggests celiac disease can present with neurological symptoms in the absence of gastrointestinal symptoms; therefore, celiac disease should be included in the differential diagnosis of CFS.

Medical Hypotheses (1999) 53(4): 347-349 - Ó1999 Harcourt Publishers Ltd. - Article No. mehy. 1998.0780
Competition For Glutathione Precursors Between The Immune System And The Skeletal Muscle: Pathogenesis Of Chronic Fatigue Syndrome
G. Bounous1, J Molson2

1 Former Professor, Department of Surgery, McGill University, and career Investigation of the Medical Research Council of Canada
2 1994 Quebec Cycling Champion. Road and Time Trial


Summary - The chronic fatigue syndrome (CFS) is typically associated or follows a recognized or presumed infection. Abnormalities of both humoral and cellular immunity have been demonstrated in a substantial proportion of patients with CFS. The most consistent findings are of impaired lymphocyte responses to mitogen. As an antioxidant, glutathione (GSH) is essential for allowing the lymphocyte to express its full potential without being hampered by oxiradical accumulation. Hence, protracted challenge of the immunocytes may lead to cellular GSH depletion. Because GSH is also essential to aerobic muscular contraction, an undesirable competition for GSH precursors between the immune and muscular systems may develop. It is conceivable that the priority of the immune system for the survival of the host has drawn to this vital area the ever-diminishing GSH precursors, thus depriving the skeletal muscle of adequate GSH precursors to sustain a normal aerobic metabolism resulting in fatigue and eventually myalgia. © 1999 Harcourt Publishers Ltd.

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GSH and Cognitive Performance

Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects
Markus CR, Olivier B, de Haan EH. [Am J Clin Nutr. 2002 Jun;75(6):1051-6.]
The negative effect of chronic stress on performance may be mediated by reduced brain serotonin function. The uptake of the serotonin precursor tryptophan into the brain depends on nutrients that influence the availability of tryptophan by changing the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). A diet-induced increase in tryptophan may increase brain serotonergic activity levels and improve cognitive performance, particularly in high stress-vulnerable subjects. We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, would increase the plasma Trp-LNAA ratio and improve cognitive performance in high stress- vulnerable subjects. A significantly greater increase in the plasma Trp-LNAA ratio after consumption of the alpha-lactalbumin diet than after the control diet was observed; memory scanning improved significantly only in the high stress-vulnerable subjects. The results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities.

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GSH and Diabetes

Diabetics are more prone to infections and circulatory problems leading to heart disease, kidney failure and blindness. Glutathione protects against the complications of diabetes.
Dietary glutathione protects rats from diabetic nephropathy and neuropathy.
Ueno Y, Kizaki M, Nakagiri R, Kamiya T, Sumi H, Osawa T. [J Nutr. 2002 May;132(5):897-900.] The aim of this study was to examine the involvement of oxidative stress in the progression of kidney dysfunction and neuropathy in diabetes and to evaluate the potential usefulness of glutathione (GSH) in diabetes. Diabetic rats were treated with 1 g/100 g GSH as a dietary supplement. GSH significantly suppressed the diabetes-induced increase in urinary 8-hydroxy-2'-deoxyguanosine, one of the markers of oxidative stress. It also prevented the diabetes-induced increases in albumin and creatinine in urine. The diabetes-induced increase in the tail flick reaction time to thermal stimuli also was normalized by treatment with dietary GSH. In conclusion, GSH treatment can beneficially affect STZ-induced diabetic rats, with preservation of in vivo renal and neural function. This suggests a potential usefulness of dietary GSH treatment to reduce diabetic complications.

Glutathione in overweight patients with poorly controlled type 2 diabetes
Aaseth J and Stoa-Birketvedt G. [Journal of Trace Elements in Experimental Medicine]. 2000; volume 13, number 1, pages 105-111. "Therapeutic trials with antioxidants that can regenerate the intracellular level of GSH [glutathione] are scarce but promising."

Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus
De Mattia G, Bravi MC, and others. [Metabolism 1998 Aug;47(8):993-7.] "In conclusion, our data support the hypothesis that abnormal intracellular GSH redox status plays an important role in reducing insulin sensitivity in NIDDM patients. Accordingly, intravenous GSH [glutathione] infusion significantly increased both intraerythrocytic GSH/GSSG ratio and total glucose uptake in the same patients."

Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipideaemic, normotensive, patients with non-insulin-dependent diabetes
De Mattia G, Bravi MC and others. [Diabetologia 1998 Nov;41(11):1392-6.] "NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology, e.g. rheumatoid arthritis, Parkinson's disease, hepatitis, liver cirrhosis, septic shock and diabetes. Our data indicate that the vascular endothelium is activated in non-insulin dependent diabetes. Antioxidant treatment counterbalanced such endothelial activation. Thus, antioxidant agents might protect against oxidant-related upregulation of endothelial adhesion molecules and slow down the progression of vascular damage in non-insulin dependent diabetes."

Glutathione in human plasma: Decline in association with aging, age- related macular degeneration, and diabetes
Samiec PS, Drews-Botsch C, and others. [Free Radic Biol Med 1998 Mar 15;24(5):699-704.] Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups, but did not reveal any difference associated with age or ARMD. In contrast, GSSG in whole blood was significantly higher in the older groups compared to the younger controls. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.

Intracellular reduced glutathione content in normal and type 2 diabetic erythrocytes: effect of insulin and (-)epicatechin
Rizvi SI, Zaid MA. [J Physiol Pharmacol 2001 Sep;52(3):483-8] Since oxidative stress has been implicated in the development of diabetic complications and GSH plays an important role in protection against oxidative damages, we have studied the in vitro effect of (-)epicatechin and insulin on the reduced glutathione content in normal and type 2 diabetic erythrocytes. The GSH content was significantly lower in type 2 diabetic patients as compared to normal individuals. In vitro insulin treatment resulted in increase in the GSH content in both normal and type 2 diabetic erythrocytes. (-)Epicatechin also resulted in an increase in erythrocyte GSH content in both normal and type 2 diabetic erythrocytes. Although the exact mechanism by which (-)epicatechin causes elevation of erythrocyte GSH is not clear nevertheless this finding may have important therapeutic implications. A higher content of dietary flavanoids may thus protect diabetic patients against long-term complications.

Apoptosis and oxidative status in peripheral blood mononuclear cells of diabetic patients
Graber R, Farine JC, and others. [Apoptosis. 1999; volume 4, number 4, pages 263- 270.]

Hyperglycemia in diabetic rats reduces the glutathione content in the aortic tissue
Tachi Y, Okuda Y, Bannai C, Bannai S, Shinohara M, Shimpuku H, Yamashita K, Ohura K. [Life Sci 2001 Jul 20;69(9):1039-47] The glutathione redox cycle plays a major role in scavenging hydrogen peroxide (H2O2) under physiological conditions. Recently, we demonstrated that a high glucose concentration in the culture medium reduced the level of H2O2 scavenging activity of human vascular smooth muscle cells (hVSMCs). We also showed that a high glucose concentration reduced the intracellular glutathione (GSH) content and the rate of uptake of cystine, which itself is a rate-limiting factor that maintains the GSH level. In the present study, we investigated whether the hyperglycemic condition in diabetic rats impairs the glutathione content in the aortic tissue in vivo. We demonstrated in vivo that the hyperglycemic condition in STZ-induced diabetic Wistar rats and OLETF rats reduced the GSH content in aortic tissue. This suggested reduced glutathione redox cycle function of aorta.

Association of Glutathione Peroxidase Activity with Insulin Resistance and Dietary Fat Intake during Normal Pregnancy
Xinhua Chen, Theresa O. Scholl, Maria J. Leskiw, Melissa R. Donaldson and T. Peter Stein [ The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5963-5968] Glutathione peroxidase (GPx) is one of the most important antioxidant enzymes in humans. We studied the relationship between erythrocyte GPx activity and fasting serum insulin, plasma glucose, and C-peptide, estimates of insulin resistance from the homeostasis model of assessment as well as dietary fat intake in 408 normotensive nondiabetic pregnant women from Camden, NJ. In conclusion, we demonstrated that normal pregnancy is associated with increased GPx activity and insulin resistance. There are ethnic differences in antioxidant response and dietary fat intake. Our findings suggest a potential link among antioxidant defenses, insulin resistance, and dietary fat intake.

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GSH, Epilepsy and Seizures

Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies
Ben-Menachem E, Kyllerman M, and others. [Epilepsy Res 2000 Jun;40(1):33-9.] "Progressive myoclonic epilepsies (EPM) are difficult to treat and refractory to most antiepileptic drugs. Besides epilepsy, EPMs also involve continuous neurological deterioration. Oxidative stress is thought to be an important factor in this process. We therefore analyzed a series of antioxidant enzymes in the blood of patients and compared with healthy age matched controls. In addition patients were given high doses of N-acetylcysteine (NAC), a glutathione percursor to determine if symptoms of EPM would improve. Five patients, four with EPM 1 (Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease) were treated with 6 g/day of NAC. NAC improved markedly and stabilized the neurological symptoms in patients with EPM 1 but had a doubtful effect in the patient with EPM 2."

Glutathione peroxidase deficiency and childhood seizures
Beutler E, Curnutte JT, Forman L. [Lancet 1991 Sep 14;338(8768):700 - Comment on: Lancet. 1991 Jun 15;337(8755):1443-4.] 4 children with intractable seizures, repeated infections, and intolerance to anticonvulsants had evidence of glutathione peroxidase deficiency. 2 had low intracellular enzyme activity but normal blood selenium and high plasma glutathione peroxidase concentrations. The other 2 had low intracellular glutathione peroxidase activity with low circulating glutathione peroxidase and selenium concentrations. The clinical state of the children improved after discontinuation of anticonvulsant medication and selenium substitution.

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Eyes and Macular Degeneration

Glutathione: a vital lens antioxidant.
Giblin FJ. [J Ocul Pharmacol Ther. 2000 Apr;16(2):121-35.] The reducing compound glutathione (GSH) exists in an unusually high concentration in the lens where it functions as an essential antioxidant vital for maintenance of the tissue's transparency. In conjunction with an active glutathione redox cycle located in the lens epithelium and superficial cortex, GSH detoxifies potentially damaging oxidants such as H2O2 and dehydroascorbic acid. Recent studies have indicated an important hydroxyl radical-scavenging function for GSH in lens epithelial cells, independent of the cells' ability to detoxify H2O2. Depletion of GSH or inhibition of the redox cycle allows low levels of oxidant to damage lens epithelial targets such as Na/K-ATPase, certain cytoskeletal proteins and proteins associated with normal membrane permeability. The level of GSH in the nucleus of the lens is relatively low, particularly in the aging lens, and exactly how the compound travels from the epithelium to the central region of the organ is not known. Recently, a cortical/nuclear barrier to GSH migration in older human lenses was demonstrated by Sweeney et al. The relatively low ratio of GSH to protein -SH in the nucleus of the lens, combined with low activity of the glutathione redox cycle in this region, makes the nucleus especially vulnerable to oxidative stress, as has been demonstrated with use of in vivo experimental animal models such as hyperbaric oxygen, UVA light and the glutathione peroxidase knockout mouse. Effects observed in these models, which are currently being utilized to investigate the mechanism of formation of human senile nuclear cataract, include an increase in lens nuclear disulfide, damage to nuclear membranes and an increase in nuclear light scattering. A need exists for development of therapeutic agents to slow age-related loss of antioxidant activity in the nucleus of the human lens to delay the onset of cataract.

strong> Protection of retinal pigment epithelium from oxidative injury by glutathione and precursors.
Sternberg P Jr, Davidson PC, Jones DP, Hagen TM, Reed RL, Drews-Botsch C. [Invest Ophthalmol Vis Sci. 1993 Dec;34(13):3661-8.]
This study was performed to examine the effect of exogenous glutathione (GSH) or its precursor amino acids on oxidative injury in cultured human retinal pigment epithelium (RPE). Added GSH provided protection at concentrations of 0.01 mM and higher. The amino acid precursors for GSH, glutamate, cysteine, and glycine also protected against injury, but this required at least 0.1 mM of each amino acid. These results indicate that protection by the amino acid precursors is mediated through synthesis of GSH, and they also show that exogenous GSH can provide protection against oxidative injury.

Glutathione in human plasma: Decline in association with aging, age- related macular degeneration, and diabetes
Samiec PS, Drews-Botsch C, and others. [Free Radic Biol Med 1998 Mar 15;24(5):699-704.] Blood samples were analyzed for GSH and GSH redox state in 40 age-related macular degeneration (ARMD) patients (> 60 y), 33 non-ARMD diabetic patients (> 60 years), 27 similarly aged non-ARMD and nondiabetic individuals (> 60 years), and 19 younger individuals (< 60 years) without ARMD or diabetes. Results showed a significantly lower plasma GSH in older individuals (ARMD, diabetes, and controls) than in younger individuals. The results suggest that in studies of age-related pathologies, oxidation of GSH may be a more important parameter than a decline in pool size, while in specific pathologies such as diabetes, both oxidation and a decline in pool size may be important.
Publication Types:
Clinical Trial
Controlled Clinical Trial

Glutathione peroxidase-1 deficiency leads to increased nuclear light scattering, membrane damage, and cataract formation in gene-knockout mice.
Reddy VN, Giblin FJ, Lin LR, Dang L, Unakar NJ, Musch DC, Boyle DL, Takemoto LJ, Ho YS, Knoernschild T, Juenemann A, Lutjen-Drecoll E. [Invest Ophthalmol Vis Sci. 2001 Dec;42(13):3247-55.] Previous in vitro studies with transgenic and gene-knockout mice have shown that lenses with elevated levels of glutathione peroxidase (GPX)-1 activity are able to resist the cytotoxic effect of H(2)O(2), compared with normal lenses and lenses from GPX-1-deficient animals. The purpose of this study was to investigate the functional role of this enzyme in antioxidant mechanisms of lens in vivo by comparing lens changes of gene-knockout mice with age-matched control animals. The results demonstrate the critical role of GPX-1 in antioxidant defense mechanisms of the lens nucleus.

Specialized protective role of mucosal glutathione in pigmented rabbit conjunctiva.
Gukasyan HJ, Kim KJ, Kannan R, Farley RA, Lee VH. [Invest Ophthalmol Vis Sci. 2003 Oct;44(10):4427-38.] To investigate mechanisms of H(2)O(2)-induced reduction in rates of active ion transport (I(sc)) across the pigmented rabbit conjunctival tissue and the protective role afforded by mucosal glutathione (GSH). ...actively secreted GSH by conjunctival epithelial cells may help reduce the injury by mucosally applied H(2)O(2). Injury by H(2)O(2) may directly affect vital membrane components (e.g., Na(+),K(+)-ATPase) involved in active ion transport across conjunctiva. Mucosal protection by GSH (or its analogues) of active conjunctival ion transport may be useful in maintaining the physiological functions of conjunctiva under oxidative stress.

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Gum Disease

High glutathione levels keep gums disease-free

26 November, 2002; BBC News World Edition - Health
People with severe gum disease have been found to have low levels of antioxidant chemicals that may offer natural protection. Periodontal (gum) disease, in which bacteria attack the teeth and gums, has been linked to both the onset of diabetes and a worsening of lung disease. Studies have even pointed to gum disease as a potential threat to unborn children. New research has found that the levels of a key antioxidant called glutathione were much higher in patients who had healthy gums. Patients with severe gum disease had very low levels of the chemical. The researchers are hopeful that they might find a way to boost antioxidant levels in patients with a treatment or diet advice.

Healthy Gums and Healthy Heart:  The role of Glutathione and its antioxidant partners

Jan. 2, 2003  Author:  Theodore Hersh, MD, MACG Professor of Medicine, Emeritus, Emory University

Epidemiological studies have revealed the association and prevalence of gingival (gum) disease and coronary artery disease in the elderly.  Studies have shown there is nearly a three-fold increase of heart disease in patients with gingivitis and periodontitis, independent of other risk factors such as tobacco abuse.

The free radicals that are generated in the inflammation process of periodontal disease promote the oxidation of plasma low density lipoproteins (LDL), which then enhance the development of atherosclerosis.  LDLs in blood transport the “bad” cholesterol, another etiologic factor in cardiovascular disease. 

Blood and tissue levels of glutathione, the body’s pivotal antioxidant, and its synergistic partners, tend to be decreased in the elderly and this decrease has been related to early senescence and various geriatric conditions.  Local and systemic repletion of glutathione and the other antioxidants in the glutathione cycle help repair gingival disease and thereby may decrease the risks of developing atherosclerosis.  This is one of the many anti-aging functions of glutathione, the body’s chief protector and detoxificant.  It reduces the inflammation present in gingival and periodontal diseases. 

In the oral cavity, glutathione has been shown to promote the normal process of attachment, spreading and growth of gingival fibroblasts, cells which are vital in periodontal tissue repair.  Tobacco (whether smoked or chewed) and betel quid chewing inhibit these tissue mechanisms and locally deplete the glutathione intracellular levels.  If the cell’s glutathione levels are low the injurious free radicals, the noxious factors, interfere with collagen synthesis and cause DNA mutations which increase the risks of developing oro-pharyngeal malignancies.  Repletion with glutathione and its endogenous antioxidant partners abolishes the damaging effects of the free radicals on the periodontal tissues, thereby, promoting functioning gingival fibroblasts.  This then promotes normal fibroblasts, which decreases the inflammation and enhances collagen synthesis vital for gum repair.  Teleologically, healthy gums lessen risks of atherosclerosis.

Periodontal disease results from invasion of pathogenic micro-organisms and bacterial toxins in the gingival causing inflammation and destruction of the connective tissue.  This generates toxic free radicals which aggravate gingival problems, while both bacteria and free radicals contribute to inflammation of arterial walls and oxidation of plasma low density lipo-proteins, liking gum disease to atherosclerosis.  The elderly are greatly afflicted by periodontal disease and loss of teeth, a condition which complicates coronary heart diseases.  Oxidative stress also accelerates gingival disease in diabetic patients and promotes the vascular complications of diabetes. 

Local antibacterial therapy and odontologic procedures are mandatory to help gingivitis and periodontitis.   The administration of antioxidants, low in senescent subjects, are adjuncts in the management of gingival disease.  Healthy gums thus may equate to a healthy heart, and glutathione therapy with its synergistic antioxidants may then maximize longevity.

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AIDS

Low glutathione levels correspond to poor survival in AIDS patients. Much documentation demonstrates the role of enhanced glutathione levels in AIDS. Proceedings of the National Academy of Science, USA 94: 1967-72, 1997

GSH and HIV - AIDS

Glutathione inhibits HIV replication by acting at late stages of the virus life cycle
Palamara AT, Perno CF, Aquaro S, Bue MC, Dini L, Garaci E. [AIDS Res Hum Retroviruses 1996 Nov 1;12(16):1537-41] We investigated the effect of glutathione on the replication of human immunodeficiency virus (HIV) in chronically infected macrophages, a known reservoir of the virus in the body.... exogenous GSH strongly suppresses the production of p24gag protein as well as the virus infectivity. This is related to a dramatic decrease in both budding and release of virus particles from chronically infected cells (either macrophages or lymphocytes)... Overall data suggest that GSH can interfere with late stages of virus replication. ...the suppression of virus replication by GSH is related to the selective inhibition of envelope glycoproteins. These results suggest a potential role of GSH in combination with other antivirals in the treatment of virus-related diseases. Intracellular glutathione as a possible direct blocker of HIV type 1 reverse transcription
Kameoka M, Okada Y, Tobiume M, Kimura T, Ikuta K. [AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1635-8.] In AIDS patients, chronic inflammation and elevated levels of cytokines seem to be associated with reduced levels of glutathione (GSH). GSH has been proposed to inhibit the activation of NF-kB, which results in the inhibition of HIV-1 replication. Here, we show the evidence that GSH and N-acetylcysteine...could inhibit the reverse transcriptase (RT) process of HIV-1.

Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte /macrophages in vitro Ho WZ, Douglas SD. [AIDS Res Hum Retroviruses 1992 Jul;8(7):1249-53] The inhibitory effects of GSH and NAC were concentration dependent. This anti-HIV-1 effect persisted in these cultures for at least 35 days without evidence of significant increase in HIV-1 expression. Thus, a single pulse exposure of HIV-1-infected monocyte/macrophages with GSH or NAC led to a sustained, concentration-dependent decrease in HIV-1 p24 antigen levels, as well as, reverse transcriptase activity without producing detectable cellular toxicity in monocyte/macrophages.

Cysteine, glutathione (GSH) and zinc and copper ions together are effective, natural, intracellular inhibitors of (AIDS) viruses
Sprietsma JE. [Med Hypotheses. 1999 Jun;52(6):529-38. Review] Comment in: Med Hypotheses. 2000 Nov;55(5):456-7. The way in which the right amount of cysteine, glutathione (GSH), and copper and zinc ions made available in the right place at the right time and in the right form can prevent an unchecked multiplication of (AIDS) viruses in a more passive or active way forms the basis for the AIDS zinc-deficiency hypothesis (A-Z hypothesis) presented in this article. Zinc and copper ions that remain available in sufficient amounts via cysteine/GSH are effective natural inhibitors/combaters of (AIDS) viruses and thereby prevent the development of chronic virus diseases that can lead to AIDS, autoimmune diseases, (food) allergies and/or cancer. A safe, relatively inexpensive and extensively tested medicine such as N-acetylcysteine (NAC) can help in supplying extra cysteine.

Glutathione deficiency is associated with impaired survival in HIV disease
Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, Deresinski SC, Herzenberg LA. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection. This finding ...establishes GSH deficiency as a key determinant of survival in HIV disease... the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.
Publication Types: Clinical Trial
Randomized Controlled Trial

Low serum thiol levels predict shorter times-to-death among HIV-infected injecting drug users
Michael Marmor, Philip Alcabes, Stephen Titus, Krystyna Frenkel, Keith Krasinski, Arthur Penn and Ronald W. Pero [AIDS 1997, 11:1389–1393] Among HIV-infected persons, low serum thiols, especially in concert with a history of AIDS, predict mortality risk. These findings support the hypothesis that oxidative stress is critical to the pathogenesis of HIV infection.

Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients
Micke P, Beeh KM, Schlaak JF, Buhl R. [Eur J Clin Invest. 2001 Feb;31(2):171-8.] HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant......different strategies to supplement cysteine supply have been suggested to increase glutathione levels in HIV-infected individuals...... to evaluate the effect of oral supplementation with two different cysteine-rich whey protein formulas on plasma GSH levels and parameters of oxidative stress and immune status in HIV-infected patients.....In glutathione-deficient patients with advanced HIV-infection, short-term oral supplementation with whey proteins increases plasma glutathione levels. A long-term clinical trial is clearly warranted to see if this "biochemical efficacy" of whey proteins translates into a more favourable course of the disease.

Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients
Micke P, Beeh KM, Buhl R. [Eur J Nutr 2002 Feb;41(1):12-8] HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. Whey proteins are rich in cysteine as well as in GSH precursor peptides. In order to evaluate the effects of whey supplementation on plasma GSH levels, HIV-infected patients were treated with whey proteins for a period of six months. Supplementation with whey proteins persistently increased plasma glutathione levels in patients with advanced HIV-infection.

Nutriceutical Modulation Of Glutathione With A Humanized Native Milk Serum Protein Isolate: Application In AIDS And Cancer
S. Baruchel, G. Viau, R. Olivier, G. Bounous, M.A. Wainberg [Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases V Luc Montagnier et al., (Ed.) Marcel Dekker Inc., New York: 447-461, 1998 . ABSTRACT V] The biological activity of the proteins isolated from cow's milk in the whey protein isolate depends on the preservation of those labile proteins which share with the predominant human milk proteins the same extremely rare glutathione (GSH)-promoting components. In a pilot study, this type of whey protein concentrate was found to be well tolerated in children with AIDS and wasting syndrome and was found associated with an improvement of the nutritional status of the patient. Moreover, the GSH promoting activity on the peripheral blood lymphocyte of this protein concentrate was validated in patients with initial low GSH levels.

Immuno-Enhancing Properties Of Undenatured Milk Serum Protein Isolate In HIV Patients.
G. Bounous [International Diary Federation: WHEY: 293-305, 1998] ABSTRACT – When GSH is depleted, as in the lymphocytes of mice during the immune response or in the lymphocyte of AIDS patients, the cysteine delivery system in a patented whey potein isolate produces a substantial increase in cellular GSH up to, but not above, normal values. Preliminary data in AIDS patients demonstrate that this is associated with major improvements in health. These clinical data and the in vitro demonstration that whey potein isolate inhibits the HIV virus while increasing GSH synthesis strongly suggest that an antagonistic relation exists between the virus and cellular GSH. Unlike specific antiretroviral drugs which may induce mutation, hence resistance of the virus to therapy, the normalization of the lymphocyte glutathione levels and redox status through a cysteine delivery system represents a totally different approach by which the natural cellular defense system is boosted. It is conceivable that GSH restoration by whey protein could prevent to a certain extent the adverse effect of AZT.

L-Glutathione decreases replication of HIV and other viruses - increases CD8 counts and function
Chen P. and Schwartz D [Int Conf AIDS 1993 (abstract PO-A13-0248)] Depletion of intracellular GSH (Glutathione)....decreases the proportion of CD8+ cells (i.e. increases the CD4/CD8 ratio) ...and inhibits ....cytotoxic T lymphocyte (CTL) activity.” Low levels of Glutathione in the cells not only decreases the total CD8 counts but decrease the functioning of the CD8 Cytotoxic T cells, that is, their ability to control the viral infections by killing the virus infected cells. Research also shows that increasing Glutathione levels reduces Tumor Necrosis Factor (TNF). High TNF levels have been linked to wasting syndrome and increased viral replication. Taking Glutathione supplements may not be an effective way to increase GSH levels due to poor assimilation.

Improvement of immune functions in HIV infection by sulfur supplementation: Two randomized trials.
Breitkreutz R, Pittack N and others. [J Mol Med 2000;78(1):55-62]. "Our findings suggest that the impairment of immunological functions in HIV+ patients results at least partly from cysteine deficiency. Because immune reconstitution is a widely accepted aim of HIV treatment, N-acetyl-cysteine [NAC] treatment may be recommended for patients with and without antiretroviral therapy. Our previous report on the massive loss of sulfur in HIV-infected subjects and the present demonstration of the immunoreconstituting effect of cysteine supplementation indicate that the HIV-induced cysteine depletion is a novel mechanism by which a virus destroys the immune defense of the host and escapes immune elimination."

Whey proteins as a food supplement in HIV-seropositive individuals.
Bounous G, Baruchel S, Falutz J, Gold P. [Clin Invest Med. 1993 Jun;16(3):204-9.] Preliminary data indicate that, in patients who maintain an adequate total caloric intake, the addition of "bioactive" whey protein concentrate as a significant portion of total protein intake increases body weight and shows elevation of glutathione (GSH) content of mononuclear cells toward normal levels.

Stanford NAC Study: Glutathione Level Predicts Survival
Author: John S. James [AIDS Treatment News; Issue: 266 03/07/97] A small randomized controlled trial of oral N-acetylcysteine(NAC) was run in San Francisco in 1993 and 1994. A report from this study was published in the PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA (1); it was also presented at a major immunology conference in San Francisco on February 22, receiving television and newspaper coverage. For persons with a CD4 count under 200, an abnormally low level of glutathione -- inside CD4 T-cells in the blood --was remarkably predictive of poor survival. (Glutathione is the major defense of those cells against oxidative stress.) Oral NAC helped to replenish low glutathione in blood cells. These findings alone do not prove that NAC is beneficial...followup studies showed that persons who were given or chose to take NAC during the trial had considerably better survival than similar subjects who did not take NAC.

N- acetylcysteine replenishes glutathione in HIV infection
De Rosa SC, Zaretsky MD, Dubs JG, and others. [Eur J Clin Invest 2000 Oct;30(10):915-29.] Comment in: Eur J Clin Invest. 2000 Oct;30(10):841-2. Studies here test oral administration of NAC for safe and effective GSH replenishment in HIV infection. NAC offers useful adjunct therapy to increase protection against oxidative stress, improve immune system function and increase detoxification of acetaminophen and other drugs. These findings suggest that NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology.
Publication Types: Clinical Trial
Randomized Controlled Trial

Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine
de Quay B, Malinverni R, Lauterburg BH. [AIDS 1992 Aug;6(8):815-9] To determine whether a single oral dose of N-acetylcysteine corrects the deficiency of cysteine and glutathione in plasma and mononuclear cells of HIV-infected patients. A single oral dose of N-acetylcysteine increased the concentration of cysteine in plasma and mononuclear cells of HIV-infected patients. Oral N-acetylcysteine transiently increases the concentrations of cysteine and glutathione in mononuclear cells of patients with HIV infection. A sustained increase in intracellular cysteine may be necessary to normalize intracellular glutathione. This may be accomplished by repeat administration of N-acetylcysteine.

HIV-induced cysteine deficiency and T-cell dysfunction--a rationale for treatment with N-acetylcysteine
Droge W, Eck HP, Mihm S. [Immunol Today. 1992 Jun;13(6):211-4.] Markedly decreased plasma cystine and cysteine concentrations have been found in HIV-infected patients at all stages of the disease and in SIV-infected rhesus macaques. The elevated glutamate levels found in the same patients aggravate the cysteine deficiency by inhibiting the membrane transport activity for cystine. The intact immune system appears to require a delicate balance between pro-oxidant and antioxidant conditions, maintained by a limited and well-regulated supply of cysteine. This balance is obviously disturbed in HIV infection and may contribute to the pathogenesis of AIDS.

Role of cysteine and glutathione in HIV infection and cancer cachexia: therapeutic intervention with N-acetylcysteine
Droge W. et al. [Adv Pharm 38: 581-600, 1997.]

Nutrition and HIV
Lichtenstein BS. [STEP Perspect. 1995 Spring;7(1):2-5.] AIDS: Nutritional status directly affects immune competence; therefore, dietary supplements can be beneficial. N-acetylcysteine (NAC), a sulfur-containing amino acid, inhibits HIV replication by raising serum glutathione levels through inhibition of TNF-a.

The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus
Baruchel S, Wainberg MA. [J Leukoc Biol 1992 Jul;52(1):111-4] This review describes the potential role of oxidative stress as a cofactor of disease progression from asymptomatic human immunodeficiency virus (HIV) infection to the acquired immunodeficiency syndrome (AIDS). An indirect argument in favor of the role of oxidative stress in HIV-associated disease progression is the consumption of glutathione (GSH), a major intracellular antioxidant, during HIV infection and progression. GSH is known to play a major role in regulation of T cell immune functions. Oxidative stress may also play an important role in the genesis of cellular DNA damage and, in this context, may be related to HIV-associated malignancies and disease progression. Finally, the role of antioxidants as components of therapeutic strategies to combat HIV disease progression is discussed.

Effects of whey protein and resistance exercise on body composition and muscle strength in women with HIV infection
Agin D, Kotler DP, Papandreou D, Liss M, Wang J, Thornton J, Gallagher D, Pierson RN Jr. [Ann N Y Acad Sci. 2000 May;904:607-9.]

Glutathione and cysteine in HIV-infected hemophiliacs
Lopez Galera RM, Juarez Gimenez JC, Montoro Ronsano JB, Segura Cardona RM, Arbos Via MA, Altisent Roca C, Tusell Puigbert JM. [Clin Chim Acta. 1996 Oct 15;254(1):63-72.]

Decreased release of glutathione into the systemic circulation of patients with HIV infection
Helbling B, von Overbeck J, Lauterburg BH. Department of Clinical Pharmacology, University of Bern, Switzerland. [Eur J Clin Invest 1996 Jan;26(1):38-44] Low glutathione (GSH) in patients with HIV infection could contribute to their immune deficiency since GSH plays an important role in the function of lymphocytes and sulphydryls decrease the expression of HIV in vitro. During infusion of GSH the concentration of cysteine in peripheral blood mononuclear cells of the HIV-infected patients increased significantly. Nevertheless, intracellular GSH did not increase. Thus, the consumption of GSH is not increased in HIV infection. Rather, the present data suggest that GSH in patients with HIV infection is low because of a decreased systemic synthesis of GSH.

Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione aerosol treatment
Holroyd KJ, Buhl R, Borok Z, Roum JH, Bokser AD, Grimes GJ, Czerski D, Cantin AM, Crystal RG. [Thorax 1993 Oct;48(10):985-9] Concentrations of glutathione, a ubiquitous tripeptide with immune enhancing and antioxidant properties, are decreased in the blood and lung epithelial lining fluid of human immunodeficiency virus (HIV) seropositive individuals. Since the lung is the most common site of infection in those who progress to AIDS it is rational to consider whether it is possible to safely augment glutathione levels in the epithelial lining fluid of HIV seropositive individuals, thus potentially improving local host defence. It is feasible and safe to use aerosolised reduced glutathione to augment the deficient glutathione levels of the lower respiratory tract of HIV seropositive individuals. It is rational to evaluate further the efficacy of this tripeptide in improving host defence in HIV seropositive individuals.

Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate
Jahoor F, Jackson A, and others. [Am J Physiol 1999 Jan;276(1 Pt 1):E205-11.] "Cysteine supplementation [by one week of NAC given to HIV-infected volunteers] elicited significant increases in both the absolute rate of synthesis and the concentration of erythrocyte glutathione. These results suggest that the glutathione deficiency of HIV infection is due in part to a reduced synthesis rate secondary to a shortage of cysteine availability." Can HIV infection be treated with antioxidants?
Muller F. Medisinsk avdeling A, Rikshospitalet, Oslo. [Tidsskr Nor Laegeforen 1995 Mar 10;115(7):835-7] Several recent reports have indicated high levels of reactive oxygen species, causing oxidative stress, in the pathogenesis of HIV infection. Oxidative stress may lead to enhanced HIV replication in infected cells and may also aggravate the immunodeficiency by reduction of cellular immunity and possibly by increased programmed cell death of lymphocytes. Moreover, reduced levels of antioxidants have been found in patients with HIV infection. This raises the question of whether antioxidant therapy might be beneficial in patients with HIV infection.

Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction
Droge W, Holm E. [FASEB J 1997 Nov;11(13):1077-89] Low NK cell activity in most cases is not life-threatening, but may be disastrous in HIV infection because it may compromise the initially stable balance between the immune system and virus, and trigger disease progression. This hypothesis is supported by the coincidence observed between the decrease of CD4+ T cells and a decrease in the plasma cystine level. In addition, recent studies revealed important clues about the role of cysteine and glutathione in the development of skeletal muscle wasting.... Cysteine supplementation may be a useful therapy if combined with disease-specific treatments such as antiviral therapy in HIV infection.

Role of cysteine and glutathione in signal transduction, immunopathology and cachexia
Droge W, Hack V, Breitkreutz R, Holm E, Shubinsky G, Schmid E, Galter D. [Biofactors 1998;8(1-2):97-102] Abnormally low plasma cystine levels have been found in the late asymptomatic stage of HIV infection and several other diseases associated with progressive loss of skeletal muscle mass. The phenomenon is commonly associated with a low NK cell activity, skeletal muscle wasting or muscle fatigue and increased rates of urea production. The low NK cell activity is in most cases not life-threatening but may be disasterous in HIV infection, because it may compromise the initially stable balance between immune system and virus and trigger disease progression.

Massive loss of sulfur in HIV infection
Breitkreutz R, Holm S, and others. [AIDS Research and Human Retroviruses. 2000; volume 16, number 3, pages 203-209] We now confirm the peripheral tissue as a site of massive cysteine catabolism in HIV infection and have determined the urinary loss of sulfur per time unit.... The peripheral tissue of HIV+ patients with or without highly active antiretroviral therapy (HAART) releases large amounts of sulfate and plasma sulfate, thioredoxin, and interleukin-6 levels are elevated in these patients. The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool."

Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice
Choi J, Leu RM, and others. [J Biol Chem 2000 Feb 4;275(5):3693-8.]

Glutathione and HIV infection: reduced reduced, or increased oxidized?
Staal FJ. [Eur J Clin Invest. 1998 Mar;28(3):194-6. Review]

Micronutrient status in relationship to mortality in HIV-1 disease
Baum MK, Shor-Posner G. [Nutr Rev. 1998 Jan;56(1 Pt 2):S135-9. Review] Antioxidant supplementation in HIV/AIDS
Segal-Isaacson AE, Rand CJ. [Nurse Pract. 1995 Jul;20(7):8, 11-4. Review.]

The role of oxidative imbalance in progression to AIDS: Effect of the thiol supplier N-acetylcysteine
Malorni W, Rivabene R, and others. [AIDS Research and Human Retroviruses. 1998; volume 14, number 17, pages 1589-1596] "Our study suggests that the redox profile of patients may be considered a predictive marker of AIDS progression and that the acute infection and the asymptomatic phase of the disease may represent a useful period in which the combined use of antiretroviral and antioxidant drugs may be beneficial."

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Heart Disease, Stroke and Cholesterol

Raised glutathione levels fight the oxidation of circulating fats in the bloodstream, including cholesterol, retarding the process of plaque formation in the arteries - the underlying cause for most heart disease and stroke.

Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients with Coronary Artery Disease

 New England Journal of Medicine

Vol. 349: 1605-1613 Oct. 23, 2003

Stefan Blankenberg, M.D., Hans J. Rupprecht, M.D., Christoph Bickel, M.D., Michael Torzewski, M.D., Gerd Hafner, M.D., Laurence Tiret, Ph.D., Marek Smieja, M.D., Ph.D., François Cambien, M.D., Jürgen Meyer, M.D., Karl J. Lackner, M.D., for the AtheroGene Investigators

ABSTRACT

Background   Cellular antioxidant enzymes such as glutathione peroxidase 1 and superoxide dismutase have a central role in the control of reactive oxygen species. In vitro data and studies in animal models suggest that these enzymes may protect against atherosclerosis, but little is known about their relevance to human disease.

Methods   We conducted a prospective study among 636 patients with suspected coronary artery disease, with a median follow-up period of 4.7 years (maximum, 5.4) to assess the risk of cardiovascular events associated with base-line erythrocyte glutathione peroxidase 1 and superoxide dismutase activity.

Results   Glutathione peroxidase 1 activity was among the strongest univariate predictors of the risk of cardiovascular events, whereas superoxide dismutase activity had no association with risk. The risk of cardiovascular events was inversely associated with increasing quartiles of glutathione peroxidase 1 activity (P for trend <0.001); patients in the highest quartile of glutathione peroxidase 1 activity had a hazard ratio of 0.29 (95 percent confidence interval, 0.15 to 0.58; P<0.001), as compared with those in the lowest quartile. Glutathione peroxidase 1 activity was affected by sex and smoking status but retained its predictive power in these subgroups. After adjustment for these and other cardiovascular risk factors, the inverse association between glutathione peroxidase 1 activity and cardiovascular events remained nearly unchanged.

Conclusions   In patients with coronary artery disease, a low level of activity of red-cell glutathione peroxidase 1 is independently associated with an increased risk of cardiovascular events. Glutathione peroxidase 1 activity may have prognostic value in addition to that of traditional risk factors. Furthermore, increasing glutathione peroxidase 1 activity might lower the risk of cardiovascular events.

Circulatory Health

Secrets of Longevity From the World’s Longest-Living People Revealed
Western researchers unravel the mysteries of the people of Okinawa.
by Ron Kennedy, M.D.

Ron Kennedy, M.D., received his certification from the American Board of Psychiatry and Neurology in 1975. Since that time, he has expanded his medical practice to cover a wide spectrum of health problems inclusive of cardiology.

Among the most interesting of recent findings from Western longevity researchers are those based on studies in Okinawa, a small island about 430 miles northeast of Taiwan and home of some of the world’s oldest and healthiest people. These findings are documented in The Okinawa Program, a massive scientific report that details why life expectancy on that small island is so long (Willcox 2001).

More centenarians live in Okinawa than any other place in the world: approximately 350% more than in the United States. The average life expectancy for Okinawan women is 86 years; for men, it is 78 years, a world record (Willcox 2001). It’s no accident: Researchers have found young-looking, clean arteries as well as healthy cholesterol, homocysteine, and blood pressure levels in these centenarians (Willcox 2001).

The Okinawan Diet: “The Antioxidant Network”

How do they do it? Perhaps the most important factor is diet. Green, leafy vegetables and high-protein foods such as fish are two staples of the Okinawan diet. These essential food groups contain an impressive array of prolongevity nutrients (Willcox 2001).

Nutrition specialists Dr. Lester Packer of the University of California, Berkeley, and Dr. Richard Passwater (1996) of Maryland’s Solgar Nutritional Research Center are calling those prolongevity nutrients the “antioxidant network.” This essential network—including vitamin groups, minerals, amino acids, and more—may be very important to longevity, as in-depth research suggests.

Amino Acids: The First Network Member

The amino acid glutathione often serves as a warrior in the body’s fight against free radicals and oxidative damage (Life Extension Foundation 1999). Glutathione is especially important to the cardiovascular system. Unfortunately, glutathione gets depleted by high levels of the compound homocysteine, which forms naturally during metabolism of another amino acid, methionine (Mayo Clinic 2002). Okinawans are able to control homocysteine levels through their low-fat, low-calorie diet (Willcox 2001).

One study, published in the American Heart Association journal Circulation, found that glutathione was able to produce a significant response in participants, especially in those people with coronary risk factors. These participants experienced an improvement in vascular function and arterial dilation (Kugiyama 1998). A report from the United Kingdom suggests that depleted glutathione levels are associated with an increased incidence of vascular cell damage. Take heart, however, as this “can be reduced when glutathione levels are restored” (Powell 2001).

Cysteine and glycine, found in foods such as fish, also are essential components of the antioxidant network (Willcox 2001). Studies are in their preliminary phases, but researchers from one prestigious East Coast medical school already have found that amino acids can be potent antioxidants. Examining the effects of these amino acids on bovine artery cells, the researchers found that cysteine and glycine are able to regulate oxidation, protect against dangerous free radicals, and boost intracellular levels of glutathione (Parinandi 1999). Researchers from the California Pacific Medical Center Research Institute have also shown that cysteine assists arterial flow and cardiovascular health in animal subjects (Holdefer 1994).

What Is Alpha-Lipoic Acid?

Once thought of as a vitamin, alpha-lipoic acid is a critical member of the antioxidant network. Many researchers tout alpha-lipoic acid as a “universal antioxidant” (Passwater 1996). It also is important to maintaining healthy levels of glutathione (Hultberg 2002).

According to Dr. Passwater (1996), alpha-lipoic acid has two primary functions: It metabolizes food, and it fights against oxidative damage. Indeed, an Italian study found that an antioxidant formula containing alpha-lipoic acid was able to promote cellular health and scavenge toxins in the bloodstream (Mosca 2002). One of the best sources of alpha-lipoic acid is high-protein foods such as fish, a mainstay of the Okinawan diet (Willcox 2001).

Vitamins and Minerals

Vitamins are likewise important antioxidant network members (Willcox 2001). A June 2002 report published in the renowned Journal of the American Medical Association provided solid affirmation of their power: Reviewing nearly 40 years of published studies, the researchers wrote of the many important benefits of several vitamin groups. “Inadequate intake of…vitamins,” they concluded, “has been linked to [many of the most prevalent health disorders in the world today]” (Fairfield 2002).

A placebo-controlled Indian study likewise gave a glowing notice for vitamins A, C, and E. Approximately 86% to 91% of the 175 subjects with cardiovascular problems saw benefits when administered these vitamins. The researchers concluded that “vitamins [A, C, and E] and fruits significantly decrease” low-density lipoprotein (“bad”) cholesterol levels and oxidation in people with cardiovascular problems (Singhal 2001).

Since Okinawans eat a diet rich in green, leafy plants, they also receive the benefits of selenium and zinc—additional components of the antioxidant network (Willcox 2001). These minerals also may reduce toxins and infections (Girodon 1997).

Maintaining Health and Longevity as Okinawans Do

Keeping optimal arterial function is an essential factor in maintaining health and longevity, and antioxidant supplementation may be one of the best ways to do so. But there is a wide array of available antioxidants, all with different specialties and benefits. Thankfully, researchers have discovered an antioxidant network that can maintain arterial health. Its dynamic formula allows you to combine the strengths of the many powerful antioxidants to reap the most fruitful rewards.

References

Fairfield, K.M. & Fletcher, R.H. (2002). “Vitamins for chronic disease prevention in adults: Scientific review.” JAMA; 287(23): 3116–26.

Girodon, F. et al. (1997). “Effect of micronutrient supplementation on infection in institutionalized elderly subjects: A controlled trial.” Annals of Nutrition & Metabolism; 41(2): 98–107.

Holdefer, M.M. et al. (1994). “Cardiotonic effects of reduced sulfhydryl amines after preservation of rabbit hearts.” Journal of Heart and Lung Transplantation; 13(1 Pt 1): 157–9.

Hultberg, B. et al. (2002). “Lipoic acid increases glutathione production and enhances the effect of mercury in human cell lines.” Toxicology; 175(1–3): 103–10.

Kugiyama, K. et al. (1998). “Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation.” Circulation; 97(23): 2299–301.

Life Extension Foundation. (1999). “How selenium fights disease.” www.lef.org/prod_desc/seleniu1.htm.

Mosca, L. et al. (2002). “Modulation of apoptosis and improved redox metabolism with the use of a new antioxidant formula.” Biochemical Pharmacology; 63(7): 1305–14.

Parinandi, N.L. et al. (1999). “Phospholipase D activation in endothelial cells is redox sensitive.” Antioxidants & Redox Signalling; 1(2): 193–210.

Passwater, R.A. (1996). “Lipoic acid basics: An interview with Dr. Jim Clark.” Whole Foods; January: 1–5.

Powell, L.A. et al. (2001). “Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions.” Free Radical Biology & Medicine; 31(10): 1149–55.

Singhal, S. et al. (2001). “Comparison of antioxidant efficacy of vitamin E, vitamin C, vitamin A, and fruits in coronary heart disease: A controlled trial.” Journal of the Association of Physicians of India; 49: 327–31.

Willcox, B.J. et al. (2001). The Okinawa Program: How the World’s Longest-Lived People Achieve Everlasting Health—and How You Can, Too. New York, NY: Clarkson Potter.

A Healthy Heart (cardiovascular disease, cholesterol, atherosclerosis, stroke, etc.)
Lowering effect of dietary milk-whey protein v. casein on plasma and liver cholesterol concentrations in rats
Zhang X, Beynen AC [Br J Nutr (1993 Jul) 70(1):139-46] The effect of dietary whey protein versus casein on plasma and liver cholesterol concentrations was investigated in female, weanling rats. Balanced, purified diets containing either whey protein or casein, or the amino acid mixtures simulating these proteins, were used. At the low dietary protein level, whey protein versus casein did not affect plasma total cholesterol, but lowered the concentration of liver cholesterol. At the high dietary-protein level, whey protein significantly lowered plasma and liver cholesterol and also plasma triacylglycerols. The hypocholesterolemic effect of whey protein was associated with a decrease in very-low-density-lipoprotein cholesterol. At the high dietary protein concentration, whey protein reduced the fecal excretion of bile acids when compared with casein. The effects of intact whey protein versus casein were not reproduced by the amino acid mixtures simulating these proteins. It is suggested tentatively that the cholesterol-lowering effect of whey protein in rats is caused by inhibition of hepatic cholesterol synthesis.

Serum Glutathione in Adolescent Males Predicts Parental Coronary Heart Disease
John A. Morrison, PhD; Donald W. Jacobsen, PhD; Dennis L. Sprecher, MD; Killian Robinson, MD; Philip Khoury, MS; Stephen R. Daniels, MD, PhD [Circulation. 1999;100:2244] Traditional risk factors account for only half of the morbidity and mortality from coronary heart disease (CHD). There is substantial evidence that oxidative injury plays a major role in the atherosclerotic process. Thus, antioxidants may protect against development of atherosclerosis. Glutathione, an intracellular tripeptide with antioxidant properties, may be protective. This study found that low tGSH in adolescent boys is a significant independent predictor of parental CHD, in addition to elevated LDL cholesterol, low HDL cholesterol, and elevated total serum homocysteine concentrations.

Oxidant stress in the vasculature
Maytin M, Leopold J, Loscalzo J. [Curr Atheroscler Rep 1999 Sep;1(2):156-64] Vascular disease and vasomotor responses are largely influenced by oxidant stress. Numerous cellular antioxidant systems exist to defend against oxidant stress; glutathione and the enzymes superoxide dismutase and glutathione peroxidase are critical for maintaining the redox balance of the cell. However, the redox state is disrupted by certain vascular diseases. It appears that oxidant stress both promotes and is induced by diseases such as hypertension, atherosclerosis, and restenosis as well as by certain risk factors for coronary artery disease including hyperlipidemia, diabetes, and cigarette smoking. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, namely adverse vessel reactivity, vascular smooth muscle cell proliferation, macrophage adhesion, platelet activation, and lipid peroxidation. Erythrocyte susceptibility to lipid peroxidation in patients with coronary atherosclerosis
Dincer Y, Akcay T, and others. [Acta Med Okayama 1999 Dec;53(6):259-64.] "Erythrocyte TBARS production was significantly higher in patients with coronary atherosclerosis than in the controls. On the other hand, the levels of plasma high-density lipoproteins, vitamin C, vitamin E and erythrocyte GSH were significantly lower, and the levels of plasma total cholesterol, triglycerides, low-density lipoproteins and TBARS were significantly higher in the patients with coronary atherosclerosis than in the controls. In conclusion, our results indicate that erythrocytes from patients with coronary atherosclerosis are more susceptible to oxidation than those of controls and that these patients have lowered antioxidant capacity as revealed by decreased plasma levels of vitamins C and E."

L-2-oxothiazolidine-4- carboxylic acid reverses endothelial dysfunction in patients with coronary artery disease
Vita JA, Frei B, and others. [J Clin Invest 1998 Mar 15;101(6):1408-14.] "Cellular redox state...is a potential target for therapy in patients with coronary artery disease." These data suggest that augmenting cellular glutathione levels improves EDNO action in human atherosclerosis. Cellular redox state may be an important regulator of EDNO action, and is a potential target for therapy in patients with coronary artery disease.

Glutathione infusion enhances coronary blood flow during oxidative stress
[Circulation 1998;97:2299-2301] Oxygen free radicals cause endothelial vasomotor dysfunction. Investigators found that reduced glutathione intravenously suppresses constriction of human coronary arteries in response to acetylcholine and increases the effect of nitroglycerin. Glutathione administration may be useful in patients with coronary artery disease, both as a result of improvement of endothelial dysfunction and augmentation of nitroglycerin-induced vasodilation and antiplatelet activity.

Serum glutathione in adolescent males predicts parental coronary heart disease
Morrison JA, Jacobsen DW, Sprecher DL, Robinson K, Khoury P, Daniels SR. [Circulation 1999 Nov 30;100(22):2244-7] There is substantial evidence that oxidative injury plays a major role in the atherosclerotic process. Thus, antioxidants may protect against development of atherosclerosis. Glutathione, an intracellular tripeptide with antioxidant properties, may be protective. This case-control study compared total serum glutathione (tGSH) in 81 adolescent male offspring of parents with premature CHD (ie, before 56 years of age) and 78 control male offspring of parents without known or suspected CHD. Case offspring had significantly lower tGSH than control offspring. Low tGSH in adolescent boys is a significant independent predictor of parental CHD, in addition to elevated LDL cholesterol, low HDL cholesterol, and elevated total serum homocysteine concentrations.

Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability
Prasad A, Andrews NP, Padder FA, Husain M, Quyyumi AA. [J Am Coll Cardiol 1999 Aug;34(2):507-14] We investigated whether glutathione (GSH), a reduced thiol that modulates redox state and forms adducts of nitric oxide (NO), improves endothelium-dependent vasomotion and NO activity in atherosclerosis. Endothelial dysfunction and reduced NO activity are associated with atherosclerosis and its clinical manifestations such as unstable angina. Thiol supplementation with GSH selectively improves human endothelial dysfunction by enhancing NO activity. Macrophage foam cell formation during early atherogenesis is determined by the balance between pro-oxidants and anti-oxidants in arterial cells and blood lipoproteins
Aviram M. [Antioxid Redox Signal 1999 Winter;1(4):585-94] Atherosclerosis is a multifactorial disease, where more than one mechanism, along more than one step, contributes to macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherogenesis. Intervention to inhibit LDL oxidation can affect the above additional LDL modifications. The balance between pro-oxidants and anti-oxidants in the LDL particle, as well as in arterial wall macrophages (such as NADPH oxidase vs. glutathione), determines the extent of LDL oxidation. Antioxidants can protect LDL from oxidation not only by their binding to the lipoprotein, but also following their accumulation in cells of the arterial wall.....the combination of antioxidants together with active paraoxonase decreases the formation of Ox-LDL and preserves PON1's ability to hydrolyze this atherogenic lipoprotein and hence, to attenuate atherosclerosis. Hyperglycemia in diabetic rats reduces the glutathione content in the aortic tissue
Tachi Y, Okuda Y, Bannai C, Bannai S, Shinohara M, Shimpuku H, Yamashita K, Ohura K. [Life Sci 2001 Jul 20;69(9):1039-47] The glutathione redox cycle plays a major role in scavenging hydrogen peroxide (H2O2) under physiological conditions. Recently, we demonstrated that a high glucose concentration in the culture medium reduced the level of H2O2 scavenging activity of human vascular smooth muscle cells (hVSMCs). We also showed that a high glucose concentration reduced the intracellular glutathione (GSH) content and the rate of uptake of cystine, which itself is a rate-limiting factor that maintains the GSH level. In the present study, we investigated whether the hyperglycemic condition in diabetic rats impairs the glutathione content in the aortic tissue in vivo. We demonstrated in vivo that the hyperglycemic condition in STZ-induced diabetic Wistar rats and OLETF rats reduced the GSH content in aortic tissue. This suggested reduced glutathione redox cycle function of aorta. Effect of administration of fermented milk containing whey protein concentrate to rats and healthy men on serum lipids and blood pressure
Kawase M, Hashimoto H, Hosoda M, Morita H, Hosono A. [J Dairy Sci 2000 Feb;83(2):255-63] The effect of fermented milk supplemented with whey protein concentrate on the serum lipid level of rats was investigated. The serum total cholesterol level for the group fed fermented milk was significantly lower than that of the control group in rats. After 8 wk, the high density lipoprotein cholesterol level for the fermented milk group showed a significant rise after 4 wk , whereas that of the placebo group showed no change even after 4 wk. The triglyceride level for the fermented milk group lowered significantly after 4 wk, whereas that of the placebo group showed no change even after 4 wk. The atherogenic index [(total cholesterol - high density lipoprotein cholesterol)/high-density lipoprotein cholesterol] for the fermented milk group decreased significantly from 4.24 to 3.52. The systolic blood pressure lowered significantly by the intake of fermented milk. On the other hand, such effect was not observed in the placebo group. These results indicate potential of the development of fermented milk with multiple therapeutic effects.

Effect of milk protein and fat intake on blood pressure and the incidence of cerebrovascular diseases in stroke-prone spontaneously hypertensive rats (SHRSP)
Ikeda K, Mochizuki S, Nara Y, Horie R, Yamori Y. [J Nutr Sci Vitaminol (Tokyo) 1987 Feb;33(1):31-6] The intake of two milk protein-rich diets containing casein and whey protein attenuated the development of severe hypertension in stroke-prone spontaneously hypertensive rats (SHRSP), and extended their life span in comparison with SHRSP on a regular stock diet. Milk fat-rich diet intake reduced the incidence of cerebrovascular disease in SHRSP without a significant fall in blood pressure. These results suggest that certain milk components have a preventive effect on hypertension and cerebrovascular disease in SHRSP.

Angiotensin I-converting enzyme inhibitory properties of whey protein digests: concentration and characterization of active peptides
Pihlanto-Leppala A, Koskinen P, Piilola K, Tupasela T, Korhonen H. [J Dairy Res 2000 Feb;67(1):53-64] The aim of this study was to identify whey-derived peptides with angiotensin I-converting enzyme (ACE) inhibitory activity. The bovine whey proteins alpha-lactalbumin and beta-lactoglobulin were hydrolysed with pepsin, trypsin, chymotrypsin, pancreatin, elastase or carboxypeptidase alone and in combination. Whey protein digests gave a 50% inhibition (IC50) of ACE activity at concentration ranges within 345-1733 micrograms/ml. The IC50 values for the 1-30 kDa fractions ranged from 485 to 1134 micrograms/ml and for the < 1 kDa fraction from 109 to 837 mg/ml. Several ACE-inhibitory peptides were isolated from the hydrolysates by reversed-phase chromatography, and the potencies of the purified peptide fractions had IC50 values of 77-1062 microM. The ACE-inhibitory peptides identified were alpha-lactalbumin fractions (50-52), (99-108) and (104-108) and beta-lactoglobulin fractions (22-25), (32-40), (81-83), (94-100), (106-111) and (142-146).

Lactokinins: whey protein-derived ACE inhibitory peptides
FitzGerald RJ, Meisel H. [Nahrung 1999 Jun;43(3):165-7] Angiotensin-I-converting enzyme (ACE) has been classically associated with the renin-angiotensin system which regulates peripheral blood pressure. Peptides derived from the major whey proteins, i.e. alpha-lactalbumin (alpha-la) and beta-lactoglobulin (beta-lg) in addition to bovine serum albumin (BSA), inhibit ACE. While they do not have the inhibitory potency of synthetic drugs commonly used in the treatment of hypertension, these naturally occurring peptides may represent nutraceutical /functional food ingredients for the prevention/treatment of high blood pressure. Studies with gastric and pancreatic proteinase digests of whey proteins indicate that enzyme specificity rather than extent of hydrolysis dictates the ACE inhibitory potency of whey hydrolysates.

Glutathione deficiencies exacerbate response to stroke
Phyllis G. Paterson, University of Saskatchewan - Saskatoon. Canada [Invited Symposium: The Therapeutic Potential of Phase II Enzyme Induction] The cascade of events responsible for the death of neural cells following a stroke include depletion of ATP, glutamate excitotoxicity, calcium overload, and production of strong oxidants that can overwhelm antioxidant defense. Glutathione (GSH) has a central role within the finely tuned network of antioxidant systems that can respond to the oxidative insult through its functions in peroxide scavenging via glutathione-S-transferase and the family of glutathione peroxidases, regeneration of alpha-tocopherol, and inhibition of NFkB which is required for the expression of pro-inflammatory genes. Our laboratory has used a nutritional approach to study the effects of GSH depletion in a rat model of stroke. We have found that a deficiency of sulfur amino acids used as a model of reduced cysteine supply for synthesis depresses GSH concentration in a number of brain regions. A second study demonstrated that acute sulfur amino acid deficiency exacerbates brain damage in a rat model of global hemispheric hypoxic ischemia. Approaches described in the literature for maintaining GSH under ischemia conditions have also been targeted towards increasing its synthesis. Administering a GSH ester immediately after an ischemic insult offered neuroprotection in one study as did the delivery of N-acetylcysteine, a compound that supports GSH synthesis by acting as a cysteine precursor. The series of studies reviewed suggests that GSH is an important determinant of the extent of secondary tissue damage in animal models of stroke. Strategies to enhance GSH in brain should be tested for their therapeutic efficacy in the human condition of stroke. (Funded by the Heart and Stroke Foundation of Saskatchewan)

Milk whey protein decreases oxygen free radical production in a murine model of chronic iron-overload cardiomyopathy
Bartfay WJ, Davis MT, Medves JM, Lugowski S. [Can J Cardiol. 2003 Sep;19(10):1163-8.]
Chronic iron overload is a major cause of organ failure worldwide, but its pathogenesis remains to be elucidated. Mice receiving iron treatments with whey supplementation had significantly lower concentrations of cytotoxic aldehydes and significantly higher cardiac levels of GPx and GSH activity than did iron-only treated mice. Additional basic research is warranted to examine the exact mechanisms by which milk whey protein protects the heart.

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Hepatitis

The liver is the major storehouse for glutathione. Glutathione is impaired in alcoholic hepatitis as well as in viral hepatitis including hepatitis A, B and C. Raised glutathione levels restore liver function. American Journal of Gastroenterology 91: 2569-2573, 1996

GSH and Hepatitis B and C

Nutritional therapy of chronic hepatitis by whey protein (non-heated)
Watanabe A, Okada K, Shimizu Y, Wakabayashi H, Higuchi K, Niiya K, Kuwabara Y, Yasuyama T, Ito H, Tsukishiro T, Kondoh Y, Emi N, Kohri H. [J Med 2000;31(5-6):283-302] In an open study the clinical efficacy of milk serum (whey) protein (cysteine content: 7.6-fold higher than that of casein) isolated from fresh milk and purified without heating was evaluated in 25 patients with chronic hepatitis B or C. Serum alanine aminotransferase (ALT) activity was reduced, and plasma glutathione (GSH) levels increased in six and five of eight patients with chronic hepatitis B, respectively, 12 weeks after the start of the supplement with Immunocal food. Serum lipid peroxide levels significantly decreased, and interleukin (IL)-2 levels and natural killer (NK) activity significantly increased. However, there were no significant whey protein-related changes in 17 patients with chronic hepatitis C. These findings suggest that the long-term supplementation with whey protein alone may be effective for improving liver dysfunctions in patients with chronic hepatitis B.
Publication Types: Clinical Trial

Lactoferrin* inhibits hepatitis C virus viremia in patients with chronic hepatitis C: a pilot study
Tanaka K, Ikeda M, Nozaki A, Kato N, Tsuda H, Saito S, Sekihara H. [Jpn J Cancer Res 1999 Apr;90(4):367-71] Hepatitis C virus (HCV) is associated with the development of cirrhosis and hepatocellular carcinoma. We recently found that bovine lactoferrin, a milk protein belonging to the iron transporter family, effectively prevented HCV infection in cultured human hepatocytes (PH5CH8). Eleven patients with chronic hepatitis C received an 8-week course of bovine lactoferrin (1.8 or 3.6 g/day). This pilot study suggests that lactoferrin is one potential candidate as an anti-HCV reagent that may be effective for the treatment of patients with chronic hepatitis.

J Clin Gastroenterol 2005 Apr;39(4):S162-6. Mitochondrial dysfunction in hepatitis C.

Korenaga M, Okuda M, Otani K, Wang T, Li Y, Weinman SA.

From the Department of Internal Medicine University of Texas Medical Branch, Galveston, TX.

Chronic hepatitis C induces a state of hepatic oxidative stress that is more pronounced than that present in many other inflammatory liver diseases. This review summarizes recent information that the hepatitis C virus (HCV) core protein plays an important role in this phenomenon. Core protein localizes to mitochondria, particularly at the points of contact between mitochondrial outer membrane and endoplasmic reticulum. Its expression causes inhibition of electron transport at complex I, increased complex I reactive oxygen species (ROS) production, decreased mitochondrial glutathione, and increased mitochondrial permeability transition in response to exogenous oxidants and tumor necrosis factor-alpha. Possible mechanisms of the core protein effects include direct interaction with electron carriers and indirect effects mediated by changes in mitochondrial calcium. These results suggest that antioxidant approaches may prove beneficial for patients with chronic hepatitis C.

PMID: 15758653 [PubMed - in process]

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GSH and the Immune System

Clin Invest Med, 12: 154-61, 1989

Immunoenhancing Property Of Dietary Whey Protein In Mice: Role Of Glutathione

G. Bounous, G. Batist, P. Gold

Montreal General Hospital, Quebec

ABSTRACT – The spleen cells immune response to sheep red blood cells of C3H/HeJ mice fed a 20 g whey protein/100 g diet is substantially higher than that of mice fed an equivalent casein diet of similar nutritional efficiency.  The present study indicates that the observed immunoenhancing effect of the whey protein mixture is dependent on the overall amino acid pattern resulting from the contribution of all its protein components.  Whey protein contains substantially more cysteine than casein.  Dietary cysteine is considered to be a rate limiting substrate for the synthesis of glutathione which is necessary for lymphocyte proliferation.  Our studies show that enhancement of host humoral immune response is associated with greater and more sustained production of splenic glutathione during the antigen driven clonal expansion of the lymphocyte in whey protein fed mice in comparison to mice fed the equivalent casein or the cysteine-enriched casein diet.  Hence the efficiency of dietary cysteine in inducing supernormal glutathione levels is greater when it is delivered in the whey protein than as free cysteine.  Administration of S-(n-butyl) homocysteine sulfoximine, which reduces splenic glutathione level by half, produces  a 4-5 fold drop in the humoral immune response of whey protein diet-fed mice.  This is further evidence of the important role of glutathione in the immunoenhancing effect of dietary whey protein.

Bounous G, Kongshavn PA, Gold P Montreal General Hospital Research Institute, Quebec, Canada."Mixing lactalbumin with either casein or soy protein in a 20 g protein/100 g diet formula significantly enhanced the immune response in comparison to that of mice fed diets containing 20% soy protein or casein."

Immunoenhancing property of dietary whey protein in mice: role of glutathione
Bounous G, Batist G, Gold P Montreal General Hospital, Quebec. "This is further evidence of the important role of glutathione in the immunoenhancing effect of dietary whey protein."

Influence Of Dietary Lactalbumin Hydrolysate On The Immune System Of Mice And Resistance To Salmonellosis
G. Bounous, M.M. Stevenson, P.A.L. Kongshavn [The Journal of Infectious Diseases, 144: 281, 1981] Our data indicate that it was possible to increase the level of this type of protein in the diet above the minimum requirement and thus produce augmented humoral immune responsiveness and resistance to salmonellosis. Lactalbumin = Whey Protein Concentrate

Functions of glutathione and glutathione disulfide in immunology and immunopathology
Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmunder H. [FASEB J. 1994 Nov;8(14):1131-8.] Even a moderate increase in the cellular cysteine supply elevates the intracellular glutathione (GSH) and glutathione disulfide (GSSG) levels and potentiates immunological functions of lymphocytes in vitro. At low GSSG levels, T cells cannot optimally activate the immunologically important transcription factor NF kappa B, whereas high GSSG levels inhibit the DNA binding activity of NF kappa B. The effector phase of cytotoxic T cell responses and IL-2-dependent functions are inhibited even by a partial depletion of the intracellular GSH pool. As signal transduction is facilitated by prooxidant conditions, we propose that the well-known immunological consequences of GSH depletion ultimately may be results of the accompanying GSSG deficiency. As HIV-infected patients and SIV-infected rhesus macaques have, on the average, significantly decreased plasma cyst(e)ine and intracellular GSH levels, we also hypothesize that AIDS may be the consequence of a GSSG deficiency as well.

Effects of purified bovine whey factors on cellular immune functions in ruminants
Wong CW, Seow HF, Husband AJ, Regester GO, Watson DL. [Vet Immunol Immunopathol. 1997 May;56(1-2):85-96.] Alpha-lactalbumin (alpha LA) exhibited an enhancing effect on IL-1 beta production. As bovine whey fractions become progressively more purified, their modulatory effects on the immune response also become more clear-cut.

Glutathione protects mice from lethal sepsis by limiting inflammation and potentiating host defense
Villa P, Saccani A, Sica A, Ghezzi P. [J Infect Dis 2002 Apr 15;185(8):1115-20] Because glutathione (GSH) is lower in sepsis, the hypothesis that GSH depletion might impair the migratory response of neutrophils to infection was tested....GSH depletion inhibited peritoneal neutrophil infiltration, increased bacterial colonies, augmented pulmonary neutrophil infiltrate, and worsened survival. Conversely, the GSH precursor N-acetyl-l-cysteine augmented neutrophil infiltration in the peritoneum but not in the lung, decreased bacterial colonies, and improved survival. Thus, migration of neutrophils to a site of infection and to a distant site is differently regulated, and optimal GSH levels are important for an efficient response to sepsis.

Glutathione-induced enhancement of neutrophil locomotion
Elferink JG, de Koster BM. [Immunobiology 1991 Dec;184(1):25-36] Both reduced glutathione (GSH) and and its oxidized form, glutathione disulfide (GSSG), enhance neutrophil locomotion. The enhancement is mainly due to a chemokinetic effect, and partly due to a chemotactic effect. GSH enhances the intracellular concentration of cGMP, which might indicate that the effect on neutrophil locomotion is mediated by an effect on cGMP.

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GSH and Infertility

Glutathione therapy for male infertility
Lenzi A, Lombardo F, Gandini L, Culasso F, Dondero F. [Arch Androl 1992 Jul-Aug;29(1):65-8]
Eleven infertile men were treated with glutathione (600 mg/day IM) for 2 months. The patients were suffering from dyspermia associated with various andrological pathologies. Standard semen and computer analyses of sperm motility were carried out before treatment and after 30 and 60 days of therapy. Glutathione exerted significant effect on sperm motility patterns. Glutathione appears to have a therapeutic effect on some andrological pathologies causing male infertility.

Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility
Lenzi A, Culasso F, Gandini L, Lombardo F, Dondero F. [Hum Reprod 1993 Oct;8(10):1657-62]
Glutathione therapy was used for 2 months in a placebo-controlled double-blind cross-over trial of 20 infertile patients with dyspermia associated with unilateral varicocele (VAR) or germ-free genital tract inflammation (INF). Glutathione therapy demonstrated a statistically significant positive effect on sperm motility, in particular on the percentage of forward motility, the kinetic parameters of the computerized analysis and on sperm morphology. The findings of this study indicate that glutathione therapy could represent a possible therapeutical tool for both of the selected andrological pathologies.
Publication Types: Clinical Trial
Randomized Controlled Trial

Glutathione treatment of dyspermia: effect on the lipoperoxidation process
Lenzi A, Picardo M, Gandini L, Lombardo F, Terminali O, Passi S, Dondero F. [Hum Reprod 1994 Nov;9(11):2044-50] We recently introduced reduced glutathione into the therapeutic protocols in some selected cases of dyspermia. This therapy improved semen quality both in a pilot follow-up study and in a double-blind cross-over trial. This improvement was seen in patients with varicocele and germ-free genital tract inflammation, two pathologies in which production of reactive oxygen species or other toxic compounds could have a pathogenic role. Polyunsaturated fatty acids of phospholipids play a major role in membrane constitution and function and are one of the main targets of the lipoperoxidative process. Therefore, to understand the therapeutic action of reduced glutathione, we selected infertile patients and studied the modifications produced by the therapy in seminal parameters, biochemical sperm membrane parameters, and the pattern of fatty acids of phospholipids from blood serum and red blood cell membranes (a model widely accepted as representative of general cell membrane status). The results showed an improvement in both sperm parameters and cell membrane characteristics. This study suggests that biochemical modifications in membrane constitution could explain the seminal results of glutathione therapy. On the other hand, it seems likely that only subjects with systemic membrane disturbances associated with andrological pathologies express this membrane damage in spermatozoa, resulting in dyspermia. This sperm alteration can be partially reversed by glutathione therapy if the structural cell membrane damage is not too severe.
Publication Types: Clinical Trial
Controlled Clinical Trial

A rationale for glutathione therapy
Lenzi A, Gandini L, Picardo M. [Hum Reprod. 1998 Jun;13(6):1419-22.] Department of Medical Pathophysiology, University of Rome La Sapienza, Italy.

Glutathione in spermatozoa and seminal plasma of infertile men
Ochsendorf FR, Buhl R, Bastlein A, Beschmann H. [Hum Reprod 1998 Feb;13(2):353-9] Zentrum Dermatologie und Venerologie, Frankfurt am Main, Germany.
Glutathione has a central role in the defence against oxidative damage; however, the data on glutathione concentrations in the semen of infertile men are limited. This study demonstrated that intracellular glutathione levels of spermatozoa are decreased in certain populations of infertile men.

Status of vitamin E and reduced glutathione in semen of oligozoospermic and azoospermic patients
A. Bhardwaj, A. Verma, S. Majumdar, K. L. Khanduja [Asian J Androl 2000 Sep; 2: 225-228]
Departments of Biophysics and Experimental Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India
Aim: To investigate the status of seminal plasma reduced glutathione (GSH) and vitamin E in three different conditions of spermatogenesis: azoospermia, oligozoospermia and normospermia. Levels of reduced glutathione were also significantly decreased in oligospermic and azoospermic group, and the reduction in azoospermic group (76.73%) was more pronounced than oligozoospermic group (62.07%). Conclusion: The decrease in reduced glutathione, an endogenous antioxidant, levels in azoospermic and oligozoospermic conditions may cause disruption in the membrane integrity of spermatozoa as a consequence of increased oxidative stress. Relationship between oxidative stress, semen characteristics, and clincial diagnosis in men undergoing infertility investigation
Pasqualotto FF, Sharma RK, Nelson DR, Thomas AJ Jr, Agarwal A. [Fertil Steril 2000;73:459-64]

Oxidative stress in normospermic men undergoing infertility evaluation
Pasqualotto FF, Sharma RK, Kobayashi H, Nelson DR, Thomas AJ Jr, Agarwal A. [J Androl. 2001 Mar-Apr;22(2):316-22] We conclude that oxidative stress is associated with male factor infertility. The presence of oxidative stress in infertile normospermic men may explain previously unexplained cases of infertility otherwise attributed to female factors.

Lipoperoxidation damage of spermatozoa polyunsaturated fatty acids (PUFA): scavenger mechanisms and possible scavenger therapies
Lenzi A, Gandini L, Picardo M, Tramer F, Sandri G, Panfili E. [Front Biosci 2000 Jan 1;5:E1-E15] The lipid metabolism in sperm cells is important both as one of the main sources for energy production and for cell structure. Testis germ cells as well as epididymal maturing spermatozoa are endowed with enzymatic and non-enzymatic scavenger systems to prevent lipoperoxidative damage. Seminal plasma also has a highly specialized scavenger system that defends the sperm membrane against lipoperoxidation and the degree of PUFA insaturation acts to achieve the same goal. Systemic predisposition and a number of pathologies can lead to an anti-oxidant/pro-oxidant disequilibrium. Scavengers, such as GSH, can be used to treat these cases as they can restore the physiological constitution of PUFA in the cell membrane. The results of GSH therapy are presented and discussed.
Publication Types: Clinical Trial

Polyunsaturated fatty acids of germ cell membranes, glutathione and blutathione-dependent enzyme-PHGPx: from basic to clinic
Lenzi A, Gandini L, Lombardo F, Picardo M, Maresca V, Panfili E, Tramer F, Boitani C, Dondero F. [Contraception 2002 Apr;65(4):301-4] Laboratory of Seminology and Immunology of Human Reproduction, Department of Medical Pathophysiology, University of Rome La Sapienza, Italy.

Biochemistry of the induction and prevention of lipoperoxidative damage in human spermatozoa
Storey BT. [Mol Hum Reprod 1997 Mar;3(3):203-13] Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia 19104-6080, USA.
Lipid peroxidation occurs in human sperm cells with damage to the cell plasma membrane, leading to loss of cytosolic components and hence to cell 'death'. Human spermatozoa possess the anti-lipoperoxidative defence enzymes, superoxide dismutase (SOD) and glutathione peroxidase plus glutathione reductase (GPX/GRD). The essential role of GPX/GRD is inferred from the observation that inhibition of GPX, either with mercaptosuccinate or with complete oxidation of intracellular reduced glutathione, results in a 20-fold increase in peroxidation rate. Human spermatozoa appear to have enough anti-lipoperoxidative defensive capacity for lifetimes long enough for fertilization but still short enough for ready removal from the female reproductive tract in good time. Too low a defence capacity could lead to male infertility.

Oxidative stress and role of antioxidants in normal and abnormal sperm function
Suresh C. Sikka, Ph.D., HCLD [Frontiers in Bioscience 1, e78-86, August 1,1996]
Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, USA
Spermatozoa, unlike other cells, are unique in structure, function, and susceptibility to damage by LPO. Mammalian spermatozoa are rich in polyunsaturated fatty acids and, thus, are very susceptible to ROS attack which results in a decreased sperm motility, presumably by a rapid loss of intracellular ATP leading to axonemal damage, decreased sperm viability, and increased midpiece morphology defects with deleterious effects on sperm capacitation and acrosome reaction. Lipid peroxidation of sperm membrane is considered to be the key mechanism of this ROS-induced sperm damage leading to infertility.

Studies on the origin of redox enzymes in seminal plasma and their relationship with results of in-vitro fertilization
Yeung CH, Cooper TG, De Geyter M, De Geyter C, Rolf C, Kamischke A, Nieschlag E.
Mol Hum Reprod. 1998 Sep;4(9):835-9.

Seminal plasma reduces exogenous oxidative damage to human sperm, determined by the measurement of DNA strand breaks and lipid peroxidation
Potts RJ, Notarianni LJ, Jefferies TM. Mutat Res. 2000 Feb 14;447(2):249-56.

Relative impact of oxidative stress on male reproductive function
Sikka SC. [Curr Med Chem. 2001 Jun;8(7):851-62.]

Male infertility: nutritional and environmental considerations
Sinclair S. [Altern Med Rev 2000 Feb;5(1):28-38] Studies confirm that male sperm counts are declining, and environmental factors, such as pesticides, exogenous estrogens, and heavy metals may negatively impact spermatogenesis. A number of nutritional therapies have been shown to improve sperm counts and sperm motility, including carnitine, arginine, zinc, selenium, and vitamin B-12. Numerous antioxidants have also proven beneficial in treating male infertility, such as vitamin C, vitamin E, glutathione, and coenzyme Q10. Acupuncture, as well as specific botanical medicines, have been documented in several studies as having a positive effect on sperm parameters. A multi-faceted therapeutic approach to improving male fertility involves identifying harmful environmental and occupational risk factors, while correcting underlying nutritional imbalances to encourage optimal sperm production and function. Magnes Res. 1994 Mar;7(1):49-57.

Red cell magnesium and glutathione peroxidase in infertile women--effects of oral supplementation with magnesium and selenium.

Howard JM, Davies S, Hunnisett A.

Biolab Medical Unit, London, UK.

Six women with a history of unexplained infertility or early miscarriage and who had failed to normalize their red blood cell magnesium (RBC-Mg) levels after four months of oral magnesium supplementation (600 mg/day) were investigated for red cell glutathione peroxidase activity (RBC-GSH-Px) and were compared with six age-matched women with a history of unexplained infertility or miscarriage who did normalize their RBC-Mg levels on magnesium supplementation. The six non-normalizers had significantly lower (P < 0.0001) RBC-GSH-Px levels than the six normalizers. After a further two months of 200 micrograms daily oral selenium as selenomethionine and oral magnesium supplements, all six women normalized their RBC-Mg (P < 0.0001) and RBC-GSH-Px (P < 0.0001) levels. All 12 previously infertile women have produced normal healthy babies all conceiving within eight months of normalizing their RBC-Mg levels. The possible relevance of these findings to the medical treatment of infertility is discussed.

PMID: 8054261 [PubMed - indexed for MEDLINE]
NOTE:  THE SELENIUM AND MAGNESIUM supplementation ELEVATED THE GSH (GLUTATHIONE LEVELS).

Even more preferrable to consume the glutathione precursors.

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GSH and Influenza Infection

Inhibition of influenza infection by glutathione.
Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. [Free Radic Biol Med. 2003 Apr 1;34(7):928-36.]
Infection by RNA virus induces oxidative stress in host cells. Accumulating evidence suggests that cellular redox status plays an important role in regulating viral replication and infectivity. In this study, experiments were performed to determine whether the thiol antioxidant glutathione (GSH) blocked influenza viral infection in cultures of Madin-Darby canine kidney cells or human small airway epithelial cells. Protection against production of active virus particles was observed at a low (0.05-0.1) multiplicity of infection (MOI). GSH inhibited expression of viral matrix protein and inhibited virally induced caspase activation and Fas upregulation. In BALB/c mice, inclusion of GSH in the drinking water decreased viral titer in both lung and trachea homogenates 4 d after intranasal inoculation with a mouse-adapted influenza strain A/X-31. Together, the data suggest that the thiol antioxidant GSH has an anti-influenza activity in vitro and in vivo. Oxidative stress or other conditions that deplete GSH in the epithelium of the oral, nasal, and upper airway may, therefore, enhance susceptibility to influenza infection.

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Kidney Disease

People with kidney failure or dialysis suffer from higher levels of oxidative stress and decreased glutathione levels. Raised glutathione levels help prevent anaemia. Nephron 61: 404-408, 1992

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Lung Disease

Doctors have used glutathione-promoting drugs to treat many lung diseases including asthma, chronic bronchitis and emphysema. Newer potential therapeutic roles can be found for cigarette smoke damage, pulmonary fibrosis and other illnesses. American Journal of Medical Science 307: 119-127, 1994

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GSH and Lupus

Clin Chem Lab Med 2002 Jul;40(7):684-8 Related Articles
Serum oxidant/antioxidant status of patients with systemic lupus erythematosus.

Taysi S, Gul M, Sari RA, Akcay F, Bakan N.

Department of Biochemistry, Faculty of Medicine, Ataturk University, Erzurum, Turkey. Seytaysi@hotmail.com

The levels of malondialdehyde and ceruloplasmin, and superoxide dismutase activity were higher, while transferrin concentration and the activities of glutathione peroxidase and catalase were lower in serum of patients with systemic lupus erythematosus (n=24) compared with healthy controls (n=20). Disease activity index correlated positively with serum malondialdehyde level (r=0.47, p<0.05), erythrocyte sedimentation rate (r=0.41, p<0.05) and C-reactive protein concentration (r=0.41, p<0.05), while it correlated negatively with serum superoxide dismutase (r=0.42, p<0.05) and glutathione peroxidase (r=-0.44, p<0.05) activities in patients. No such correlations were found in healthy control subjects. It remains to be seen whether correlations found between disease activity score and serum malondialdehyde level, and also activities of serum superoxide dismutase and glutathione peroxidase enzymes observed in the present study may be used to predict prognosis in patients with systemic lupus erythematosus.

PMID: 12241014 [PubMed - in process]

 

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Meniere's Disease

The role of free radicals and plasmatic antioxidant in Meniere’s syndrome.         

Raponi G, Alpini D, Volonte S, Capobianco S, Cesarani A.

Vertigo Center, S. Rita Hospital, Milan, Italy. xrapon@tin.it

The objective of this study was verification, through suitable hematochemical tests, of the supposition that central-systemic microtoxicosis plays a role either in the etiopathogenesis of Meniere's syndrome or in labyrinthine pathological processes or hypoacusis. We did not, therefore, exclude other well-known hypotheses in the causality of these pathologies. Nonetheless, one finds, particularly in the Meniere's cases, a constant homogeneous distribution of the metabolic products of this microtoxicosis, such as a high concentration of free radicals and low natural defenses (e.g., antioxidant plasmatic capacity). Therefore, there exists a kind of dangerous central and systemic presence of reactive molecules, aimed toward the polyunsaturated fatty acids and homeostatic complex enzymes, that is not compensated for by the natural antioxidant defense. The presence of this lack of balance, verified by suitable tests, has shown the rationality of use of a product made from reduced glutathione, thioctic acid, cysteine, and other antioxidants as a multipurpose antidote to this element of etiopathogenesis. Patients were divided into three groups (control, conventional therapy, and antioxidant treatment), and those in the antioxidant treatment group, especially those with Meniere's syndrome, demonstrated a net and more significant improvement. Also, parallel clinical and instrument evaluations of this new therapeutic solution, the efficacy of which has already been positively demonstrated, are expected to provide further evidence to support the primary hypothesis.

PMID: 15106283 [PubMed - indexed for MEDLINE]

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Glutathione (GSH) Deficiency and the Pathogenesis of Multiple Sclerosis

Recent findings in tissue from multiple sclerosis victims corroborate the mechanisms documented in a growing body of research based evidence as to the steps leading to disease expression.  “Observed depletion of GSH, elevation of ceramide level and apoptosis in banked human brains from patients with neuroinflammatory diseases (e.g. x-adrenoleukodystrophy and multiple sclerosis) suggest that the intracellular level of GSH may play a crucial role in the regulation of cytokine-induced generation of ceramide leading to apoptosis of brain cells in these diseases.”

Cytokine, tumor necrosis factor‑alpha (TNF-a) or interleukin-1 beta (IL‑1b)‑mediated activation of sphingomyelinases (SMases), leads to degradation of sphingomyelin to ceramide, a sphingolipid 1,2, and the universal lipid second messenger.  This potentiated a 2-fold increase in H2O2 generation, leading to lipid peroxidation and loss of activity of respiratory chain complex IV in the GSH depleted state compared to GSH-replete mitochondria 3.  “Mitochondria are a target of ceramide produced in the signaling of TNF.3”  Pretreatment of cells so as to increase intracellular GSH inhibited the TNF-a-induced sphingomyelin hydrolysis and ceramide generation as well as cell death 4. 

 The literature implicates excessive or inappropriate generation of nitric oxide (NO) in Parkinson’s Disease, Alzheimer’s Disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis 5.  “Human astrocytes released abundant NO upon stimulation with the pro-inflammatory cytokine (IL)‑1b, which was potentiated by interferon (IFN)-gamma and TNF-a.  IL-1 receptor antagonist protein markedly attenuated astrocyte NO production.6”  “It is now well documented that NO and its toxic metabolite, peroxynitrite (ONOO-–) can inhibit components of the mitochondrial respiratory chain...5”  “...neurones, in contrast to astrocytes, appear particularly vulnerable to the action of these molecules.5”   “...the susceptibility of different brain cells to NO and ONOO– exposure may be dependent on factors such as the intracellular GSH concentration...5”  “Evidence is now available to support this scenario for neurological disorders, such as multiple sclerosis.5”

Variable vulnerability to oxidative stress has been well documented in various neurological cell types.  “Astrocytes maintain high intracellular concentrations of certain antioxidants, making these cells resistant to oxidative stress relative to oligodendrocytes and neurons.7”  In fact, astrocytes appear to play a central role in the antioxidant defense of the brain.7  One of the major antioxidants used by astrocytes is GSH and, “...astroglial cells prefer cystine from [instead of] cysteine for GSH synthesis...8”

Other conditions give insight into the effect of GSH on SMases and ceramide.  “Cell culture studies of hypoxic PC12 cell death...suggest that GSH protects cells from hypoxic injury by direct inhibition of neutral SMases activity and ceramide formation...9”  This protection appears to be lost in MS patients as GSH is decreased in plaques10, and was absent in the CSF in MS.11  Protective mechanisms involving GSH appear to occur in MS, “...blood GSH was increased (p<0.01) [in MS] during exacerbation and remission as well.  This rise in this thiol is likely to be a compensatory mechanism defending the cells from further oxidant injuries.12”

The relationship between cytokines and GSH has been demonstrated in cell cultures of TNF-resistant (TNFr) and TNF-sensative (TNFs) cell lines.  “The basic level of GSH was significantly higher in the TNFr cells than in TNFs cells.  Treatment with 20 microM ceramide decreased cellular GSH in TNFs cells by 50% in contrast to an insignificant decrease in the TNFr cells.13”   

Also, the effect of intracellular GSH on neutrophil and lymphoid apoptosis give further insight into the crucial regulator role played by this important thiol.  “Because apoptosis is a critical mechanism regulating PMN survival in vivo, manipulation of PMN intracellular thiols may represent a novel therapeutic target for the regulation of cellular function.14”  “Thiol compounds, such as L-cysteine and GSH, play crucial roles in the regulation of lymphocyte proliferation.15”  “These data suggest that the inability to neutralize oxidative stress results in the apoptosis of lymphoid cells under L-cystine-and GSH-depleted conditions.  The protective effects of rADF may be explained by...enhancing the L-cystine internalization and elevating the intracellular GSH content.15”  © 2000 AmmunoMed, LLC. 

1. Singh, I., Pahan, K., Khan, M., Singh, AK.  Cytokine-mediated induction of ceramide is redox-sensitive.  Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases.  J Biol Chem. 273(32): 20354-62,  Aug 7, 1998.

2. Xu, J., Yeh, CH, Chen, S., He, L., Sensi, SL., Canzoniero, LM, Choi, DW., Hsu, CY.  Involvement of de novo ceramide biosynthesis in tumor necrosis factor-alpha/cycloheximide-induced cerebral endothelial cell death.  J Biol Chem. 273(26): 16521-6,  June 26, 1998.

3. Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., Fernandez-Checa, JC.  Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species.  Role of mitochondrial glutathione.  J Biol Chem.  272(17): 11369-77, Apr 25, 1997.

4. Liu, B., Andrieu,Abadie, N., Levade, T., Zhang, P., Obeid, LM., Hannun, YA.  Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death.  J Biol Chem.  273(18): 11313-20, May 1, 1998.

5.  Heales, SJ., Bolanos, JP., Stewart, VC., Brookes, PS., Land, JM.., Clark, JB.  Nitric oxide, mitochondria and neurological disease.  Biochim Biophys Acta.  1410(2): 215-28, Feb 9, 1999.

6. Hu, S., Sheng, WS., Peterson, PK., Chao, CC.  Differential regulation by cytokines of human astrocyte nitric oxide production.  Glia. 15(4): 491-4, Dec 1995.

7. Wilson, John X.  Antioxidant defense of the brain: a role for astrocytes1.  Can. J. Physiol. Pharmacol. 75: 1149-1163, 1997.

8. Kranich, O., Dringen, R., Sandberg, M., Hamprecht, B.  Utilization of cysteine andcysteine precursors for the synthesis of glutathione in astroglial cultures: preference for cystine.  Glia. 22(1): 11-8, Jan. 1998.

9. Yoshimura, S., Banno, Y., Nakashima, S., Hayashi, K., Yamakawa, H., Sawada, M., Sakai, N., Nozawa, Y.  Inhibition of neutral sphingomyelinase activation and ceramide formation by glutathione in hypoxic PC12 cell death.   J Neurochem. 73(2): 675-83, Aug. 1999

10. Langemann, H., Kabiersch, A., Newcombe, J.  Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis.  Eur Neurol. 32(5): 248-52, 1992.

11. Ronquist, G., Frithz, G.  Adenylate kinase activity and glutathione concentration of cerebrospinal fluid in different neurological disorders.  Eur Neurol. 18(2): 106-10, 1979.

12. Karg, E., Klivenyi, P., Nemeth, I., Bencski, K., Pinter, S., Vecsei, L.  Nonenzymatic antioxidants of blood in multiple sclerosis.  J Neurol. 246(7): 533-9, July 1999.

13. Davis, MA., Flaws, JA., Young, M., Collins, K., Colburn, NH.  Effect of ceramide on intracellular glutathione determines apoptotic or necrotic cell death of JB6 tumor cells.  Toxicol Sci. 53(1): 48-55, Jan. 2000.

14. Watson, RW., Rotstein, OD., Nathens, AB., Dackiw, AP., Marshall, JC.  Thiol-mediated redox regulation of neutrophil apoptosis.  Surgery.  120(2): 150-7; discussion 157-8, Aug. 1996. 

15. Iwata, S., Hori, T., Sato, N., Hirota, K., Sasada, T., Mitsui, A., Hirakawa, T., Yodoi, J.  Adult T cell leukemia (ATL)-derived factor/human thioredoxin prevents apoptosis of lymphoid cells induced by L-cystine and glutathione depletion: possible involvement of thiol-mediated redox regulation in apoptosis caused by pro-oxidant state.  J Immunol. 158(7): 3108-17, April 1, 1997.

J Neurosci Res. 2002 Nov 15;70(4):580-7.

Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels.

Calabrese V, Scapagnini G, Ravagna A, Bella R, Foresti R, Bates TE, Giuffrida Stella AM, Pennisi G.

Biochemistry and Molecular Biology Section, Department of Chemistry, Faculty of Medicine, University of Catania, Catania, Italy.

Nitric oxide (NO) is hypothesized to play a role in the immunopathogenesis of multiple sclerosis (MS). Increased levels of NO metabolites have been found in patients with MS. Peroxynitrite, generated by the reaction of NO with superoxide at sites of inflammation, is a strong oxidant capable of damaging tissues and cells. Inducible NO synthase (iNOS) is up-regulated in the CNS of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In this study, Western blots of cerebrospinal fluid (CSF) from patients with MS demonstrated the presence of iNOS, which was absent in CSF from control subjects. There was also NOS activity present in both MS and control CSF. Total NOS activity was increased (by 24%) in the CSF from MS patients compared with matched controls. The addition of 0.1 mM ITU (a specific iNOS inhibitor) to the samples did not change the activity of the control samples but decreased the NOS activity in the MS samples to almost control levels. The addition of 1 mM L-NMMA (a nonisoform specific NOS inhibitor), completely inhibited NOS activity in CSF from control and MS subjects. Nitrotyrosine immunostaining of CSF proteins was detectable in controls but was greatly increased in MS samples. There were also significant increases in CSF nitrate + nitrite and oxidant-enhanced luminescence in MS samples compared with controls. Additionally, a significant decrease in reduced glutathione and significant increases in oxidized glutathione and S-nitrosothiols were found in MS samples compared with controls. Parallel changes in NO metabolites were observed in the plasma of MS patients, compared with controls, and accompanied a significant increase of reduced glutathione. These data strongly support a role for nitrosative stress in the pathogenesis of MS and indicate that therapeutic strategies focussed on decreasing production of NO by iNOS and/or scavenging peroxynitrite may be useful in alleviating the neurological impairments that occur during MS relapse. Copyright 2002 Wiley-Liss, Inc.

Publication Types:

• Clinical Trial
• Controlled Clinical Trial

PMID: 12404512 [PubMed - indexed for MEDLINE]

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Neurological Disease

Low glutathione levels have been associated with neuro-degenerative diseases such as MS (Multiple Sclerosis), ALS (Lou Gehrig's disease), Alzheimer's disease and Parkinson's disease, among others. The Lancet 344: 796-798, 1994

Glutathione, Oxidative Stress and Neurodegeneration

Schulz JB, Lindenau J, Seyfried J, Dichgans [J.Eur J Biochem 2000 Aug;267(16):4904-11] There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.

Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients
Perry TL, Yong VW. [Neurosci Lett 1986 Jun 30;67(3):269-74] A significant deficiency of GSH was found in the substantia nigra, but not in 5 other brain regions of PD patients, nor in PSP patients' brains. Glutathione transferase activity was similar in the substantia nigra of PD, PSP and control patients. Since total GSH is consumed only by conjugation in detoxification processes, nigral GSH deficiency in PD patients implies continued local presence of a possible causative neurotoxin up to the time of death.

Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia
Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD [Ann Neurol, 36(3):348-55 1994 Sep] Reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were measured in various brain areas (substantia nigra, putamen, caudate nucleus, globus pallidus, and cerebral cortex) from patients dying with Parkinson's disease, progressive supranuclear palsy, multiple-system atrophy, and Huntington's disease and from control subjects with no neuropathological changes in substantia nigra. GSH levels were reduced in substantia nigra in Parkinson's disease patients ..... the level of GSH in the substantia nigra was significantly reduced only in Parkinson's disease. This suggests that the change in GSH in Parkinson's disease is not solely due to nigral cell death, or entirely explained by drug therapy, for multiple-system atrophy patients were also treated with levodopa. The altered GSH/GSSG ratio in the substantia nigra in Parkinson's disease is consistent with the concept of oxidative stress as a major component in the pathogenesis of nigral cell death in Parkinson's disease.

Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease
Jenner P, Dexter DT, Sian J, Schapira AH, Marsden CD [Ann Neurol 1992;32 Suppl:S82-7]. We examine the evidence for free radical involvement and oxidative stress in the pathological process underlying Parkinson's disease, from postmortem brain tissue. The concept of free radical involvement is supported by enhanced basal lipid peroxidation in substantia nigra in patients with Parkinson's disease, demonstrated by increased levels of malondialdehyde and lipid hydroperoxides. Levels of reduced glutathione are decreased in nigra in Parkinson's disease; this decrease does not occur in other brain areas or in other neurodegenerative illnesses affecting this brain region (i.e., multiple system atrophy, progressive supranuclear palsy). Altered glutathione metabolism may prevent inactivation of hydrogen peroxide and enhance formation of toxic hydroxyl radicals. In brain material from patients with incidental Lewy body disease (presymptomatic Parkinson's disease), there is no evidence for alterations in iron metabolism and no significant change in mitochondrial complex I function. The levels of reduced glutathione in substantia nigra, however, are reduced to the same extent as in advanced Parkinson's disease. These data suggest that changes in glutathione function are an early component of the pathological process of Parkinson's disease.

Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson's disease
Merad-Boudia M, Nicole A, Santiard-Baron D, Saille C, Ceballos-Picot I. [Biochem Pharmacol 1998 Sep 1;56(5):645-55] In Parkinson's disease (PD), dopaminergic cell death in the substantia nigra was associated with a profound glutathione (GSH) decrease and a mitochondrial dysfunction. The fall in GSH concentration seemed to appear before the mitochondrial impairment and the cellular death, suggesting that a link may exist between these events.An approach to determine the role of GSH in the mitochondrial function and in neurodegeneration was to create a selective depletion of GSH in a neuronal cell line in culture..... This treatment led to a nearly complete GSH depletion after 24 hr and induced cellular death via an apoptotic pathway after 5 days of BSO treatment.... rapid GSH depletion was accompanied, early in the process, by a strong and transient intracellular increase in reactive oxygen species.... These results showed the crucial role of GSH for maintaining the integrity of mitochondrial function in neuronal cells. Oxidative stress and mitochondrial impairment, preceding DNA fragmentation, could be early events in the apoptotic process induced by GSH depletion. Our data are consistent with the hypothesis that GSH depletion could contribute to neuronal apoptosis in Parkinson's disease through oxidative stress and mitochondrial dysfunction.

Does oxidative stress participate in nerve cell death in Parkinson's disease?
Hirsch EC. [Eur Neurol 1993;33 Suppl 1:52-9] Parkinson's disease is characterized by a massive neuronal loss in several cell groups of the midbrain. However, the most consistent lesions are observed in dopaminergic systems including nigral neurons. Although the cause of this neuronal loss remains unknown, oxidative stress has been suspected to participate in the mechanism of nerve cell death for several reasons. (1) Lipid peroxidation, a consequence of oxygen free radical production, has been found to be elevated in the substantia nigra in Parkinson's disease. (2) Catecholaminergic neurons containing neuromelanin, an autooxidation by-product of catecholamines, are more vulnerable in Parkinson's disease than non-melanized catecholaminergic neurons. (3) Catecholaminergic neurons surrounded by a low density of cells containing glutathione peroxidase, a free radical scavenging enzyme, are more susceptible to degeneration in Parkinson's disease than those well protected against oxidative stress. (4) The content of iron, a compound which exacerbates the production of free radicals in catecholaminergic neurons, is increased in the substantia nigra in Parkinson's disease. It remains, however, to be determined whether oxidative stress participates to the cause of the disease or only represents a consequence of nerve cell death.

Altered mitochondrial function, iron metabolism and glutathione levels in Parkinson's disease
Jenner P. [Acta Neurol Scand Suppl 1993;146:6-13] The mechanisms underlying dopamine cell death in substantia nigra in Parkinson's disease remain unknown. Current concepts of this process suggest the involvement of free radical species and oxidative stress. ...there is evidence for inhibition of complex I of the mitochondrial respiratory chain, altered iron metabolism and decreased levels of reduced glutathione. However,.... alterations in iron may be a response to, rather than a cause of nigral cell death....However, there is a reduction in the levels of reduced glutathione in substantia nigra in incidental Lewy body disease of the same magnitude as occurs in advanced Parkinson's disease. This would suggest that alterations in glutathione function are an early marker of pathology in Parkinson's disease and may be a clue to the primary cause of nigral cell death.

Depletion of brain glutathione potentiates the effect of 6-hydroxydopamine in a rat model of Parkinson's disease
Garcia JC, Remires D, Leiva A, Gonzalez R.[ J Mol Neurosci 2000 Jun;14(3):147-53] "The study examines the possible role of rat brain glutathione depletion by diethyl maleate (DEM) in the potentiation of 6-hydroxydopamine (6-OHDA) neurotoxicity, .....DEM injury makes the animals more susceptible to brain-oxidative damage by 6-OHDA, which can indicate that in the double-damaged animal group, DEM could induce potentiation of the toxicity through striatal glutathione depletion.

Decreased glutathione results in calcium-mediated cell death in PC12
Jurma OP, Hom DG, Andersen JK. [Free Radic Biol Med 1997;23(7):1055-66] Neuronal damage in certain cellular populations in the brain has been linked to oxidative stress accompanied by an elevation in intracellular calcium. Many questions remain about how such oxidative stress occurs and how it affects calcium homeostasis. Glutathione (GSH) is a major regulator of cellular redox status in the brain, and lowered GSH levels have been associated with dopaminergic cell loss in Parkinson's disease (PD). We found that transfection of antisense oligomers directed against glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, into PC12 cells resulted in decreased GSH and increased levels of ROS. Decreased GSH levels also correlated with an increase in intracellular calcium levels. Data from this study suggest that dopaminergic neurons are very sensitive to decreases in the internal oxidant buffering capacity of the cell caused by reductions in GSH levels, and that alterations in this parameter can result in disruption of calcium homeostasis and cell death. These results may be of particular significance for therapeutic treatment of PD, as those dopaminergic neurons that are spared in this disorder appear to contain the calcium binding protein, calbindin.

Glutathione depletion switches nitric oxide neurotrophic effects to cell death in midbrain cultures: implications for Parkinson's disease
Canals S, Casarejos MJ, de Bernardo S, Rodriguez-Martin E, Mena MA. [J Neurochem. 2001 Dec;79(6):1183-95.] Nitric oxide (NO) exerts neurotrophic and neurotoxic effects on dopamine (DA) function in primary midbrain cultures. We investigate herein the role of glutathione (GSH) homeostasis in the neurotrophic effects of NO. This study shows that alterations in GSH levels change the neurotrophic effects of NO in midbrain cultures into neurotoxic. Under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterized by an early step of free radicals production followed by a late requirement for signalling on the sGC/cGMP/PKG pathway.

Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease
Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, Greenamyre JT, Liu RM, Forman HJ, Andersen JK. [J Biol Chem. 2000 Aug 25;275(34):26096-101] Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. These results suggest that the early observed GSH losses in the SN may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with PD.

[Case-control study of markers of oxidative stress and metabolism of blood iron in Parkinson's disease]
Larumbe Ilundain R, Ferrer Valls JV, Vines Rueda JJ, Guerrero D, Fraile P. [Rev Esp Salud Publica 2001 Jan-Feb;75(1):43-53] Increasingly growing evidence exists of the involvement of oxidative stress mechanisms in Parkinson's disease. However, few studies have been made of levels of antioxidants in the peripheral bloodstream and of the influence of the intake of nutrients on the development of this disease. Significant differences were found in the plasma levels of GSH between cases and controls. The results of this study support the possible involvement of oxidative stress in the pathogenesis of Parkinson's disease and reveal, in turn, alterations in some peripheral blood parameters in keeping with known findings in the sustantia nigra.

Neurodegenerative Diseases – Alzheimer’s and Parkinson’s

By Patricia A.L. Kongshavn, Ph.D.

Alzheimer’s and Parkinson’s are neurodegenerative diseases in which cell damage and degeneration is seen in certain specific areas of the brain. In Parkinson’s disease nerve cells slowly degenerate in the part of the mid-brain (the substantia nigra layer of the basal ganglia) that controls movement, resulting in progressive loss of muscular coordination and balance. In Alzheimer’s disease brain cells degenerate, brain mass shrinks and characteristic neurofibrillary tangles and neural plaques are seen post mortem.

Increasing lines of evidence suggest that mitochondrial damage plays a key role in Parkinson’s, Alzheimer’s and some other neurodegenerative diseases (1-5). This, in turn, increases the generation of reactive oxygen species and the onset of oxidative stress, leading to oxidative damage and programmed cell death. At the same time, glutathione homeostasis is disturbed (6-9). In one study, glutathione levels were reduced by 40% in the substantia nigra in early stage Parkinson’s disease (7). These levels fall even much further in later stages, the magnitude of reduction in glutathione seeming to parallel the severity of the disease (9). The lowered glutathione values and increased oxidative stress are thought to be responsible for the loss of dopamine producing cells in the substantia nigra in Parkinson’s disease patients (7, 8).

The use of antioxidants, particularly glutathione, for the treatment of neurodegenerative  diseases is an obvious consideration (6-9). In an in vitro study, glutathione was shown to protect human neural cells from apoptosis i.e. cell death, induced by dopamine (8). Sechi et al. showed that intravenous injection of glutathione was effective in reducing symptoms (42% decline in disability) in early Parkinson’s disease patients and possibly retarded the progression of the disease (9). Other treatment options to increase brain concentrations of glutathione are better choices for long-term treatment. Banaclocha has reviewed the putative usefulness of N-acetyl cysteine for this purpose in the treatment of Parkinson’s, Alzheimer’s and other age-associated neurodegenerative diseases (1). Immunocal is an even better choice than this drug, being entirely non-toxic and proven to raise intracellular glutathione (10).

References. 1. Banaclocha, MM. Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases. Med Hypotheses 56:472-477, 2001.

2. Schultz JB, Lindenau J, Seyfried J et al. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904-4911, 2000.

3. Jenner P, Olanow CW Neurology 47:S1161-S170, 1996.

4. Kidd PM. Parkinson’s disease as a multifactorial oxidative neurodegeneration: implications for integrative management. Altern Med Rev 5:501, 2000.

5. Lohr JB, Browning JA Free radical involvement in neuropsychiatric illnesses. Psychopharmacol Bull 31:159-165, 1995. 6. Reid M, Jahoor F. Glutathione in disease. Curr Opin Clin Nutr Metab Care 4:65-71, 2001.

7. Sian J, Dexter DT, Lees AJ, et al. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 348-355, 1994.

8. Gabby M, Tauber M.Porat S et al. Selective role of glutathione in protecting human neuronal cells from dopamine-induced apoptosis. Neuropharmacology 35:571-578, 1996.

9. Sechi G, Deledda MG, Bua G et al. Reduced intravenous glutathione in the treatment of early Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 20: 1159-1170, 1996.

10. Lands L, Grey VL, and Smountas AA Effect of supplementation with a cysteine donor on muscular performance. J Appl Physiol 87:1381-1385, 1999.

J Neurol Sci. 2003 Mar 15;207(1-2):51-8.

Mitochondrial dysfunction and death in motor neurons exposed to the glutathione-depleting agent ethacrynic acid.

Rizzardini M, Lupi M, Bernasconi S, Mangolini A, Cantoni L.

Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy.

This study investigated the mechanisms of toxicity of glutathione (GSH) depletion in one cell type, the motor neuron.

Ethacrynic acid (EA) (100 microM) was added to immortalized mouse motor neurons (NSC-34) to deplete both cytosolic and mitochondrial glutathione rapidly.

This caused a drop in GSH to 25% of the initial level in 1 h and complete loss in 4 h. This effect was accompanied by enhanced generation of reactive oxygen species (ROS) with a peak after 2 h of exposure, and by signs of mitochondrial dysfunction such as a decrease in 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide (MTT) (30% less after 4 h). The increase in ROS and the MTT reduction were both EA concentration-dependent. Expression of heme oxygenase-1 (HO-1), a marker of oxidative stress, also increased.

The mitochondrial damage was monitored by measuring the mitochondrial membrane potential (MMP) from the uptake of rhodamine 123 into mitochondria. MMP dropped (20%) after only 1 h exposure to EA, and slowly continued to decline until 3 h, with a steep drop at 5 h (50% decrease), i.e. after the complete GSH loss.

Quantification of DNA fragmentation by the TUNEL technique showed that the proportion of cells with fragmented nuclei rose from 10% after 5 h EA exposure to about 65% at 18 h. These results indicate that EA-induced GSH depletion rapidly impairs the mitochondrial function of motor neurons, and this precedes cell death.  

This experimental model of oxidative toxicity could be useful to study mechanisms of diseases like spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS), where motor neurons are the vulnerable population and oxidative stress has a pathogenic role.

PMID: 12614931 [PubMed - indexed for MEDLINE]

Early activation of antioxidant mechanisms in muscle of mutant Cu/Zn-superoxide dismutase-linked amyotrophic lateral sclerosis mice.

Jokic N, Di Scala F, Dupuis L, Rene F, Muller A, De Aguilar JL, Loeffler JP.

Laboratoire de Signalisations Moleculaires et Neurodegenerescence, Universite Louis Pasteur, Faculte de Medecine, 11 rue Humann, 67085 Strasbourg, France.

A subset of familial ALS cases is associated with missense mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1), a free radical scavenging enzyme that protects cells against oxidative stress.

Overexpression of these ALS-linked mutations confers an unidentified gain of function to the enzyme that triggers a series of neurological disorders characteristic of human ALS.

To understand how skeletal muscle may counteract the progression of the disease, we explored the expression of different molecular effectors involved in antioxidant pathways.  

Our results are strongly indicative of the early and long-lasting activation of a series of molecular effectors thought to act coordinately in preventing the increased oxidative stress characteristic of ALS.

PMID: 15033789 [PubMed - indexed for MEDLINE]

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GSH and Bone Density - Osteoporosis

Milk basic protein promotes bone formation and suppresses bone resorption in healthy adult men
Toba Y, Takada Y, Matsuoka Y, Morita Y, Motouri M, Hirai T, Suguri T, Aoe S, Kawakami H, Kumegawa M, Takeuchi A, Itabashi A. [Biosci Biotechnol Biochem. 2001 Jun;65(6):1353-7.] In the previous in vitro and in vivo studies, we have shown that milk whey protein, especially its basic protein fraction (milk basic protein [MBP]), promoted bone formation and suppressed bone resorption. This present study examines the effect of MBP on the biochemical markers of bone metabolism in healthy adult men. The results suggest that MBP promoted bone formation and suppressed bone resorption, while maintaining the balance of bone remodeling.

Controlled trial of the effects of milk basic protein (MBP) supplementation on bone metabolism in healthy adult women
Aoe S, Toba Y, Yamamura J, Kawakami H, Yahiro M, Kumegawa M, Itabashi A, Takada Y. [Biosci Biotechnol Biochem. 2001 Apr;65(4):913-8.] Recent in vitro and in vivo studies showed that milk whey protein, especially its basic protein fraction, contains several components capable of both promoting bone formation and inhibiting bone resorption. The object of this study was to examine the effects of MBP on bone metabolism of healthy adult women. A daily MBP supplementation of 40 mg in healthy adult women can significantly increase their BMD independent of dietary intake of minerals and vitamins. This increase in BMD might be primarily mediated through inhibition of osteoclast-mediated bone resorption by the MBP supplementation.


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Glutathione System in Defense of Prostate Problems

By Patricia A.L. Kongshavn, Ph.D.

Prostate hypertrophy (enlargement) is more often benign than malignant. It is age related, increasing to over 80% in men over 80. Several factors are related to this condition, one being male hormones (androgens) and another being deficiencies in glutathione (GSH) enzymes, in particular GSH-S-transferases. It has been proposed that deficiency in this glutathione enzyme system increases the likelihood of developing both an enlarged prostate and prostate cancer (1).

In addition to the traditional treatments (surgical removal, laser therapy, radiotherapy, chemotherapy and hormonal treatment) for prostate cancer, a number of alternative or complementary therapies are gaining acceptance. One is diet (low fat, high fiber) and another is the use of antioxidants including vitamin A, lycopene and selenium. A recent study by the National Cancer Institute showed that selenium supplementation dramatically reduced the incidence of prostate cancer (2) and others have confirmed that higher selenium levels in individuals correlated with a decreased risk of developing advanced prostate cancer (3). It is noteworthy that selenium is an integral part of GSH peroxidase, the enzyme that mediates antioxidation by glutathione.

Androgens have been reported to stimulate free radical damage and deplete glutathione in human prostate cancer cells (4). Given the natural decline of glutathione levels with aging, it is suggested that androgens induce pro-oxidative stress, which, unopposed by a weakened glutathione system, contributes to the development of prostate cancer.

Studies are in progress to investigate the benefit of using Immunocal as a complementary treatment for prostate cancer since this dietary supplement is already proven to raise intracellular glutathione in normal adults (5). A number of case reports describing the beneficial effects of this treatment in prostate cancer patients have recently been published by Bounous (6). In these patients PSA (prostate specific antigen) values fell, indicating reduction of the tumor mass.

Immunocal is also indicated for use as a prophylaxis against benign hypertrophy as well as cancer since both conditions appear to be related to deficiency in the glutathione enzyme system.

In summary, there is increasing evidence that the glutathione system provides a vitally important defense against prostate problems. Therefore, dietary treatments to support or enhance this system, in particular Immunocal. and selenium, could be very important in maintaining a healthy gland as well as providing protection against the development of prostate cancer.

References
1. Moskaluk CA, Duray PH, Cowan KH et al. Immunohistochemical expression of pi-class glutathione S-transferase is down-regulated in adenocarcinoma of the prostate. Cancer 79:1595-1599,1997.

2. Clark LC, Dalkin B, Krongrad A et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 81:730-734,1998.

3. Yoshizawa K, Willett WC, Morris SJ et al. Study of prediagnostic selenium levels in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 90:1219-1224,1998.

4. Ripple MO, Henry WF, Randall P et al. Pro-oxidant-antioxidant shift induced by androgen treatment of human prostate carcinoma cells. J Natl Cancer Inst 89:40-48,1997.

5. Lands LC, Grey VL, Smountas AA. Effect of supplementation with a cysteine donor. J Appl Physiol 87:1381-1385,1997.

6. Bounous G. Whey protein concentrate (WPC) and glutathione modulation in cancer treatment. Anticancer Res 20: 4785-92,2000.

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Aging

It is well known that a gain in age is accompanied by a precipitous fall in glutathione levels. Lower glutathione levels are implicated in many diseases associated with aging including cataracts, Alzheimer's disease, Parkinson's, atherosclerosis and others. Journal of Clinical Epidemiology 47: 1021-25, 1994

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Antioxidant Functions

Antioxidants are well documented and known to possess vital roles in health maintenance and disease prevention. Glutathione is your cell's own major antioxidant. Maintaining elevated glutathione levels aids the body's natural antioxidant function. Biochemical Pharmacology 47: 2113-2121, 1994

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Athletic Performance

Raised glutathione levels helps increase strength and endurance. Those interested in physical fitness can benefit from a definite athletic edge. Journal of Applied Physiology 87: 1381-1385, 1999

Glutathione in Athletic Performance, Endurance and Sports Nutrition
The effect of whey protein supplementation with and without creatine monohydrate combined with resistance training on lean tissue mass and muscle strength

Burke DG, Chilibeck PD, Davidson KS, Candow DG, Farthing J, Smith-Palmer T. Department of Human Kinetics, St. Francis Xavier University, Antigonish, Nova Scotia, B2G 2W5, Canada. [1: Int J Sport Nutr Exerc Metab 2001 Sep;11(3):349-64] Males that supplemented with whey protein while resistance training demonstrated greater improvement in knee extension peak torque and lean tissue mass than males engaged in training alone. Males that supplemented with a combination of whey protein and creatine had greater increases in lean tissue mass and bench press than those who supplemented with only whey protein or placebo.

Physical exercise intensity can be related to plasma glutathione levels
Gambelunghe C, Rossi R, Micheletti A, Mariucci G, Rufini S. [J Physiol Biochem 2001 Mar;57(2):9-14] The aim of the present study was to examine the effect of different kinds of physical exercise on plasma glutathione levels. Our results suggest that GSH plays a central antioxidant role in blood during intensive physical exercise and that its modifications are closely related to exercise intensity.

Oxidants, antioxidant nutrients and the athlete
Packer L. [Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.] Strenuous physical exercise induces oxidative stress. Severe or prolonged exercise can overwhelm antioxidant defences, which include vitamins E and C and thiol antioxidants, which are interlinked in an antioxidant network, as well as antioxidant enzymes. Evidence for oxidative stress and damage during exercise comes from direct measurement of free radicals, from measurement of damage to lipids and DNA, and from measurement of antioxidant redox status, especially glutathione. There is little evidence that antioxidant supplementation can improve performance, but a large body of work suggests that bolstering antioxidant defences may ameliorate exercise-induced damage, suggesting that the benefits of antioxidant intervention may be for the long term rather than the short term.

Antioxidants and physical performance
Clarkson PM. Department of Exercise Science, University of Massachusetts, Amherst 01003, USA.[Crit Rev Food Sci Nutr 1995 Jan;35(1-2):131-41] Performance of strenuous physical activity can increase oxygen consumption by 10- to 15-fold over rest to meet energy demands. The resulting elevated oxygen consumption produces an "oxidative stress" that leads to the generation of free radicals and lipid peroxidation. A defense system of free radical scavengers minimizes these dangerous radicals. Changes in antioxidant scavengers and associated enzymes (e.g., glutathione, tocopherol, glutathione peroxidase) also provide clues about demands on the defense system. Physical training has been shown to result in an augmented antioxidant system and a reduction in lipid peroxidation. Supplementation with antioxidants appears to reduce lipid peroxidation but has not been shown to enhance exercise performance. The "weekend athlete" may not have the augmented antioxidant defense system produced through continued training. This may make them more susceptible to oxidative stress. Whether athletes or recreational exercisers should take antioxidant supplements remains controversial. However, it is important that those who exercise regularly or occasionally ingest foods rich in antioxidants.

Mitochondria changes in human muscle after prolonged exercise, endurance training and selenium supplementation
Zamora AJ, Tessier F, Marconnet P, Margaritis I, Marini JF. [Eur J Appl Physiol 1995;71(6):505-11] The functional and structural responses to acute exercise (E) and training, (T) with or without selenium supplementation (Sel), were investigated in a double-blind study on 24 young male subjects. The results in Sel would seem to suggest a dampening effect of the selenium on the mitochondria changes, both in chronic and acute exercise. The mechanism of this action on mitochondrial turnover is uncertain, but might be related to a higher efficiency of the selenium-dependent enzyme glutathione peroxidase.

Reductions in blood glutamine concentration following intense exercise may contribute to immune suppression in overtrained athletes

• Plasma amino acid concentrations in the overtraining syndrome: Possible effects on the immune system
  Parry-Billings M, Budgett R, Koutedakis K et al (1992). [Medicine and Science in Sports and Exercise 24, 1353-8] Overtraining and long-term exercise are associated with an impairment of immune function. We provide evidence in support of the hypothesis that the supply of glutamine, a key fuel for cells of the immune system, is impaired in these conditions and that this may contribute to immunosuppression. Plasma glutamine concentration was decreased in overtrained athletes and after long-term exercise (marathon race) and was increased after short-term, high intensity exercise (sprinting). Branched chain amino acid supplementation during long-term exercise was shown to prevent this decrease in the plasma glutamine level. Given the proposed importance of glutamine for cells of the immune system, it is concluded that the decrease in plasma glutamine concentration in overtraining and following long-term exercise, and not an intrinsic defect in T lymphocyte function, may contribute to the immune deficiency reported in these conditions.

• Immunological hazards from nutritional imbalance in athletes
  Shephard RJ, Shek PN. [Exerc Immunol Rev 1998;4:22-48] This review examines the influences of nutritional imbalance on immune function of competitive athletes, who may adopt an unusual diet in an attempt to enhance performance. Since endurance exercise leads to protein catabolism, an athlete may need 2.0 g/kg protein rather than the 0.7-1.0 g/kg recommended for a sedentary individual. Both sustained exercise and overtraining reduce plasma glutamine levels, which may contribute to suppressed immune function postexercise. Vitamins are important to immune function because of their antioxidant role. However, the clinical benefits of vitamin C supplementation are not enhanced by the use of more complex vitamin mixtures, and excessive vitamin E can have negative effects. Iron, selenium, zinc, calcium, and magnesium ion all influence immune function. Supplements may be required after heavy sweating, but an excessive intake of iron facilitates bacterial growth.

• Glutamine, exercise and immune function. Links and possible mechanisms
  Walsh NP, Blannin AK, Robson PJ, Gleeson M. [Sports Med 1998 Sep;26(3):177-91] Glutamine is the most abundant free amino acid in human muscle and plasma and is utilised at high rates by rapidly dividing cells, including leucocytes, to provide energy and optimal conditions for nucleotide biosynthesis. Falls in the plasma glutamine level have been reported following endurance events and prolonged exercise. These levels remain unchanged or temporarily elevated after short term, high intensity exercise. Plasma glutamine has also been reported to fall in patients with untreated diabetes mellitus, in diet-induced metabolic acidosis and in the recovery period following high intensity intermittent exercise. Furthermore, athletes experiencing discomfort from the overtraining syndrome exhibit lower resting levels of plasma glutamine than active healthy controls. Therefore, physical activity directly affects the availability of glutamine to the leucocytes and thus may influence immune function.

• Does endurance exercise impair glutamine metabolism?
  Parry-Billings M, Blomstrand E, Leighton B et al (1990). Canadian Journal of Sport Science 13, 13P (abstract)

• Plasma glutamine changes after high intensity exercise in elite male swimmers. Kargotich S, Rowbottom DG, Keast D et al (1996). Medicine and Science in Sport and Exercise 28, S133 (abstract)

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Colostrum and Our Bio-Active Protein Comparison

Cystine is essential to the immune system.  But, the proteins in colostrum have almost no cystine content.  In addition, research published by one manufacturer of colostrum, in The Vital Health News, Winter 1998 edition, page 7, demonstrated that "the effectiveness of the immune factors present in colostrum is lowered by stomach acid."  Colostrum, which is produced during the first 26 hours following birth by the mammary glands, is primarily composed of immunoglobulin and some lactoferrin.  According to both laboratory experiments and clinical trials conducted in Germany, colostrum supplementation was associated with mild increases in immune function in some patients, but these increases were not statistically significant (p=ns). 

Since the primary mechanism of action on the immune system is through stimulation of the production of glutathione, the near absence of glutathione precursors in the immunoglobulin fraction  of colostrum may explain its relative lack of efficiency.  Our bio-active protein contains substantial amounts of alpha lactalbumin, lactoferrin and serum albumin, which contain high levels of cystine residues.  According to the US Physician's Desk Reference, cystine is the preferred form of cysteine for the synthesis of glutathione in macrophages and astrocytes.   This allows these cells to provide cysteine to lymphocytes and neurons directly upon demand. 

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Healthy Elderly Women

High Blood Glutathione Levels Accompany Excellent Physical and Mental Health in Women Ages 60 to 103 Years

Calvin A. Lang
Betty Jane Mills
Helen L. Lang
Marica C. Liu
Wayne M. Usui
John Richie Jr
Walter Mastropaolo
Stanley A. Murrell

Louisville, Kentucky

Abstract

Earlier we found a high percentage of subnormal total glutathione (G^T) levels in blood from elderly subjects and patients with chronic diseases. These findings suggested a hypothesis that high levels of G^T in the blood occur in old persons who are in excellent physical and mental health. To this end, we recruited 87 white women who ranged in age from 60 to 103 years and reported that they felt healthy. Their health was verified with physical examinations, clinical chemistry profiles, psychosocial assessments, and blood G^T determinations. This evaluation was performed in three waves over a 5-year period. The values were compared with those from representative individuals in this region and with normal national data. The results verified that these healthy subjects were in top physical and mental health. We also found that subjects of all ages had very high blood G^T levels in waves I and II but only normal levels in wave III. These findings confirm that high blood G^T concentrations and excellent physical and mental health are characteristics of long-lived women. (J Lab Clin Med 2002;140:413-7)

Publishing and Reprint Information

From the Departments of Biochemistry and Molecular Biology, Pathology, and Psychological and Brain Sciences, University of Louisville. Supported in part by funding from the Retirement Research Foundation, Chicago, Ill. Submitted for publication September 5, 2001. Revision submitted May 10, 2002. Accepted May 15, 2002. Reprint requests: Calvin A. Lang, ScD, Department of Biochemistry, MDR 412, University of Louisville, Louisville, KY 40292; e-mail: calang@louisville.edu

Copyright © 2002 by Mosby, Inc. All rights reserved.

doi:10.1067/mlc.2002.129504   Articles with References to this Article

This article is referenced by these articles:
Glutathione: A marker and antioxidant for aging
Journal of Laboratory and Clinical Medicine
December 2002 • Volume 140 • Number 6
Ravinder J. Singh  

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Detoxification with GSH

Cysteine metabolism and metal toxicity
Quig D. [Altern Med Rev 1998 Aug;3(4):262-70] The pro-oxidative effects of metals are compounded by the fact that the metals also inhibit antioxidative enzymes and deplete intracellular glutathione. Cysteine has a pivotal role in inducible, endogenous detoxication mechanisms in the body, and metal exposure taxes cysteine status. Basic research pertaining to the transport of toxic metals into the brain is summarized, and a case is made for the use of hydrolyzed whey protein to support metal detoxification and neurological function. Early detection and treatment of metal burden is important for successful detoxification, and optimization of nutritional status is paramount to the prevention and treatment of metal toxicity.

Mechanism of action and value of N- acetylcysteine in the treatment of early and late acetaminophen poisoning: A critical review.
Jones AL. [Journal of Toxicology -- Clinical Toxicology. 1998; volume 36, number 4, pages 277-285] The mechanism of action of N-acetylcysteine in early acetaminophen poisoning is well understood, but much remains to be learned of the mechanism of its possible benefit in acetaminophen poisoning presenting beyond 15 hours. Candidate mechanisms for a beneficial effect in-clude improvement of liver blood flow, glutathione replenishment, modification of cytokine production, and free radical or oxygen scavenging.

Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity.
Lauterburg BH and Velez ME. [Gut. 1998; volume 29, pages 1153-1157]. "The data indicate that low glutathione may be a risk factor for [acetaminophen] hepatotoxicity in alcoholics because a lower dose of [acetaminophen] will be necessary to deplete glutathione below the critical threshold concentration where hepatocellular necrosis starts to occur."

Chronic ethanol and nicotine interaction on rat tissue antioxidant defense system.
Husain K, Scott BR, Reddy SK, Somani SM. [Alcohol. 2001 Oct;25(2):89-97.] This study was undertaken to examine the interactive effects of chronic ethanol and nicotine consumption on the antioxidant defense system in different tissues of rat. Chronic ingestion of ethanol resulted in a significant depletion of glutathione (GSH) content in liver, lung, and testes, whereas chronic administration of nicotine significantly depleted GSH content in liver and testes. The combination of ethanol plus nicotine resulted in a significant depletion of GSH content in liver, lung, and testes. Chronic ingestion of ethanol resulted in a significant decrease in glutathione peroxidase (GSH-Px) activity in liver and kidney, whereas a combination of ethanol plus nicotine increased GSH-Px activity in liver and decreased GSH-Px activity in kidney and testes. Ethanol, nicotine, or a combination of ethanol plus nicotine significantly increased lipid peroxidation, respectively, in liver. It is suggested that prolonged exposure to ethanol and nicotine produce similar, and in some cases additive, oxidative tissue injuries in rat.

Treatment of sulfur mustard (HD)-induced lung injury.
Anderson DR, Byers SL, Vesely KR. [J Appl Toxicol 2000 Dec;20(S1):S129-S132] An in vivo sulfur mustard (HD) vapor exposure model followed by bronchoalveolar lavage was developed previously in this laboratory to study biochemical indicators of HD-induced lung injury. This model was used to test two treatment compounds-niacinamide (NIA) and N-acetyl cysteine (NAC)-for their ability to ameliorate HD-induced biochemical changes. These results show that NAC may be useful as a potential treatment compound for HD-induced lung injury.

Role of glutathione redox cycle and catalase in defense against oxidative stress induced by endosulfan in adrenocortical cells of rainbow trout (Oncorhynchus mykiss).
Dorval J, Hontela A. [Toxicol Appl Pharmacol. 2003 Oct 15;192(2):191-200.]
The role of antioxidants in maintaining the functional integrity of adrenocortical cells during in vitro exposure to endosulfan, an organochlorine pesticide, was investigated in rainbow trout (Oncorhynchus mykiss). ...protection against the adrenal toxicity of endosulfan, a pesticide that impairs cell viabilityand cortisol secretion. CAT, GPx, and GSH were identified as important antioxidants in maintaining the function and integrity of rainbow trout adrenocortical cells and ATA, L-BSO, and NAC were identified as effective modulators of CAT and GSH redox cycle. Moreover, this study suggests that the glutathione redox cycle may be more efficient than catalase in protecting adrenocortical cells against endosulfan-induced oxidative stress.

Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity
Patrick L. [Altern Med Rev. 2003 May;8(2):106-28.] Exposure to toxic metals has become an increasingly recognized source of illness worldwide. Both cadmium and arsenic are ubiquitous in the environment, and exposure through food and water as well as occupational sources can contribute to a well-defined spectrum of disease. The mechanisms of arsenic- and cadmium-induced damage include the production of free radicals that alter mitochondrial activity and genetic information. The metabolism and excretion of these heavy metals depend on the presence of antioxidants and thiols that aid arsenic methylation and both arsenic and cadmium metallothionein-binding. S-adenosylmethionine, lipoic acid, glutathione, selenium, zinc, N-acetylcysteine (NAC), methionine, cysteine, alpha-tocopherol, and ascorbic acid have specific roles in the mitigation of heavy metal toxicity. Several antioxidants including NAC, zinc, methionine, and cysteine, when used in conjunction with standard chelating agents, can improve the mobilization and excretion of arsenic and cadmium.

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Intravenous GSH, NAC, Cysteine, Methionine vs. Immunocal

Increasing Intracellular Glutathione with Cysteine and Cysteine Pro-Drugs 

A number of strategies have been tried to increase glutathione.  Most approaches use pharmacological doses of glutathione or a form of the rate limiting substrate, cysteine.  Administering GSH by oral, intravenous, intratracheal, and intraperitoneal routes has been tried but has no lasting effect.^76,77 Glutathione is digested if taken orally, has a short half-life if delivered intravenously and does not significantly increase liver or lymphocyte GSH if given intratracheally or intraperitoneally.  Esterified GSH compounds have increased GSH in a few tissues⁷⁸ but have limited value in human use due to harmful and potentially toxic metabolic products.⁷⁹

Providing cysteine or methionine directly is associated with significant toxicity.⁸⁰ Cysteine is readily metabolized⁷⁷ and methionine can be converted to cysteine in the liver but this requires energy. Also, the conversion process could increase an intermediate metabolite, homocysteine.  If it is not fully metabolized, increased levels of homocysteine leads to homocysteinuria that appears to be associated with atherosclerotic vascular disease.

N-acetyl cysteine (NAC) has been used for treatment of AIDS to increase GSH.^{3, 28, 81-6}   However, NAC has only 10% bioavailability when given orally and is associated with significant side effects (rashes and severe gastro-intestinal upset) at therapeutic doses of 4 grams or more per day.³⁹ Anaphylactic reactions have also been reported.⁸⁷ 

Even at more moderate pharmacological doses, cysteine pro-drugs, such as NAC, are associated with mobilization of heavy metals across the placenta^88-90 and blood brain barrier,^91-5 as well as into liver, kidney⁸⁵ and astrocytes.⁹⁶ Though this may prove useful for some interventional techniques, it may also limit its usefulness as a daily source of cysteine for GSH enhancement.  Various forms of cysteine, including NAC, cause excitotoxin release in certain areas of the brain such as the hippocampus. The hippocampus is the location of neurodegeneratation in Alzheimer’s disease. One of the leading theories advanced to explain the cause of neurodegenerative diseases is excitotoxin release.⁹⁷ Excitotoxin release has been documented with various forms of cysteine but does not occur with cystine.⁹⁸

Cystine is the Optimal Form of Cysteine for Intracellular Glutathione Synthesis.

Cystine has been shown to be the cysteine precursor of choice in macrophages³² and astroglial cells,^{69, 70} which then feed cysteine to lymphocytes and neurons, respectively, in a highly regulated fashion.  The increase in the GSH levels in astrocytes is substantially greater with cystine than with any other cysteine source.⁶⁹ Therefore, cystine represents the optimal form of cysteine for GSH production in the antigen presenting macrophage and the neuron protecting astroglial cell.

One way to avoid the multiple drawbacks of using pharmacological doses of cysteine pro-drugs is to use an undenatured source of complete amino acids containing a high concentration of cystine, which is now available (Immunocal^®, Immunotec Research Ltd., Montreal, Quebec, Canada).  The effectiveness of this particular approach of GSH production is well documented,⁹⁹ and the glutathione produced by this method has been shown to be beneficial in patients suffering from AIDS with wasting syndrome.¹⁰⁰

The bioactivity and effectiveness of Immunocal^® appears to be dependent on the undenatured quality of this amino acid delivery system that results in preservation of the disulfide bond that allows a high concentration of cystine to be made available to the liver.  This is not a property found in commercial whey proteins. 

75. Kudsk, K.A., Minard, G., Croce, M.A., Brown, R.O., Lowrey, T.S., Pritchard, E., Dickerson, R.N., Fabian, T.C.   A randomized trial of isonitrogenous enteral diets after severe trauma.  Annals of Surgery 224 (4): 531-543, 1996.

76. Witschi, A., Reddy, S., Stofer, B., Lauterburg, B.H.  The systemic availability of oral glutathione.  Europ. J. Clin. Pharmacol. 43: 667-669, 1992.

77.  Bray, T.M., Taylor, C.O.  Enhancement of tissue glutathione for antioxidant and immune functions in malnutrition.  Biochem. Pharmacol. 47: 2113-2123, 1994.

78.  Puri, R.N., Meister, A., Transport of glutathione as g-glutamylcysteinylglycylester, into liver and kidney.  Proc. Natl. Acad. Sci. U.S.A. 80: 5258-5260, 1983.

79.  Anderson, M.E., Powric, F., Puri, R.N., Meister, A.  Glutathione monoethyl ester: Preparation, uptake by tissues, and conversion to glutathione.  Arch. Biochem Biophys.  239: 538-548, 1985.

80.  Birnbaum, S.M., Winitz, M., Greenstein, J.P.  Quantitative nutritional studies with water-soluble, chemically defined diets. III. Individual amino acids as sources of “non-essential” nitrogen.  Arch. Biochem. Biophys. 72:  428-436, 1957.

81. Dröge, W., Gross, A., Hack, V., Kinscherf, R., Schykowski, M., Bockstette, M., Mihm, S., Galter, D.  Role of cysteine and glutathione in HIV infection and cancer cachexia: therapeutic intervention with N-acetylcysteine.  Adv. Pharmacol. 38: 581-600, 1997. 82. Gross, A., Hack, V., Stahl-Hennig, C., Dröge, W.  Elevated hepatic g-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIV-infected rhesus macaques.  AIDS Res.Hum. Retroviruses 12 (17): 1639-1641, Nov 20, 1996.

83. Kinscherf, R., Fischbach, T., Mihm, S., Roth, S., Hohenhaus-Sievert, E., Weiss, C., Edler, L., Bartsch, P., Dröge, W.  Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells.  FASEB J. 8 (6): 448-451, April 1994.

84.  Staal, F.J.T., Roederer, M., Herzenberg, L.A., Herzenberg, L.A.  Intracellular thiols regulate activation of nuclear factor kB and transcription of human immunodeficiency virus.  Proc. Natl. Acad. Sci. U.S.A.  87: 9943-9947, Dec. 1990.

85.  Roederer, M., Staal, F.J.T., Raju, P.A., Ela, S.W., Herzenberg, L.A., Herzenberg, L.A.  Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine.  Proc. Natl. Acad. Sci. U.S.A.  87: 4884-4888, June 1990. 86.  Kalebic, T., Kinter, A., Poli, G., Anderson, M.E., Meister, A., Fauci, A.S.  Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine.  Proc. Natl. Acad. Sci. U.S.A.  88: 986-990, Feb. 1991.

87.  Mant, T.G.K., Tempowski, J.H., Volans, G.N., Talbot, J.C.C.  Adverse reactions to acetylcysteine and effects of overdose.  Br. Med. J.  289: 217-219, 1984.

88.  Kajiwara, Y., Yasutake, A., Adachi, T., Hirayama, K.  Methylmercury transport across the placenta via neutral amino acid carrier.  Arch. Toxicol.  70: 310-314, 1996.

89.  Aschner, M., Clarkson, T.W.  Mercury 203 distribution in pregnant and nonpregnant rats following systemic infusions with thiol-containing amino acids.  Teratology 36: 321-328, 1987.

90.  Aschner, M., Clarkson, T.W.  Distribution of mercury 203 in pregnant rats and their fetuses following systemic infusions with thiol-containing amino acids and glutathione during late gestation.  Teratology 38:  145-155, Aug. 1988.

91.  Aschner, M., Clarkson, T.W.  Methyl mercury uptake across bovine brain capillary endothelial cells in vitro: the role of amino acids.  Pharmacol. Toxicol.  64: 293-297, Mar. 1989.

92.  Mokrzan, E.M., Kerper, L.E., Ballatori, N., Clarkson, T.W.  Methylmercury-thiol uptake into cultured brain capillary endothelial cells on amino acid system L.  J. Pharmacol. Exp. Ther. 272: 1277-1284, Mar. 1995.

93.  Aschner, M., Clarkson, T.W.  Uptake of methylmercury in the rat brain: effects of amino acids.  Brain Res.  462: 31-39, Oct. 1988.

94.  Kerper L.E., Ballatori, N., Clarkson, T.W.  Methylmercury transport across the blood-brain barrier by an amino acid carrier.  Am. J. Physiol.  262: R761-R765, May 1992.

95.  Aschner, M.  Brain, kidney and liver 203 Hg-methyl mercury uptakes in the rat: relationship to the neutral amino acid carrier.  Pharmacol. Toxicol.  65: 17-20, July 1989.

96.  Aschner, M., Eberle, N.B., Goderie, S., Kimelberg, H.K.  Methylmercury uptake in rat primary astrocyte cultures: the role of the neutral amino acid transport system.  Brain Res.  521:  221-228, June 1990.

97.  Blaylock, R. L. Excitotoxins: The Taste that Kills. Health Press, Santa Fe, N.M. 1997.

98.  Abbas, A.K., Jardemark, K., Lehmann, A., Weber, S.G., Sandberg, M.  Bicarbonate-sensitive cysteine induced elevation of extracellular aspartate and glutamate in rat hippocampus in vitro.  Neurochem. Int.  30:  253-259, Mar. 1997.

99. Bounous, G., Batist, G., Gold, P.  Immunoenhancing property of dietary whey protein in mice: Role of glutathione.  Clinical and Investigative Medicine 12: 154-161, 1989.

100.  Bounous, G., Baruchel, S., Falutz, J., Gold, P.  Whey protein as a food supplement in HIV-seropositive individuals.  Clin. Invest. Med.  16: 204-209, 1993. 101.  Baruchel, S., Viau, G., Olivier, R., Bounous, G., Wainberg, M.  Chapter 42: Nutriceutical modulation of glutathione with a humanized native milk serum protein isolate, Immunocal™: Application in AIDS and Cancer.  Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases.  Edited by: Montagnier, L., Oliver, R., Pasquier, C. Dec. 1997.

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Maintaining Health

1: J Nutr. 2004 Mar;134(3):489-92. Publication Types: Tutorial  PMID: 14988435 [PubMed] Glutathione metabolism and its implications for health.

 Faculty of Nutrition, Texas A&M University, College Station, TX, 77843, USA. g-wu@tamu.edu :Wu G, Fang YZ, Yang S, Lupton JR, Turner ND.

Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase.  

Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation).

Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.

A nutraceutical,  bonded cystine delivery system, developed at McGill University Medical Research Center is a very effective and safe way to elevate “Glutathione” in every human cell. Immunotec Research, in conjunction with McGill University Medical Research Center in Montreal, Canada have tested the bio-active protein, proving with a Method of Use patent, (pharmaceutical patent), that it can elevate cellular glutathione.

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Pregnancy, Lactation and Childbirth

Glutathione's role in fetal and placental development is crucial. It also acts in the placenta to detoxify pollutants before they can reach the developing child. Many complications of pregnancy have been linked with poor glutathione levels. Early Human Development 37: 167-174, 1994

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Toxins, Pollution and Radiation

Glutathione detoxifies a variety of pollutants, carcinogens and poisons, including many found in fuel exhaust and cigarette smoke. It also retards damage from radiation exposure due to the eroding ozone layer. Annual Reviews of Biochemistry 52: 711-760, 1983

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