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 placenta88-90 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-glutamylcysteinylglycyl ester, 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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