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Glutathione |
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Glutathione is a tripeptide (composed of 3 amino acids) that is considered to be one of the best natural antioxidant available to date. It is synthesized by the body from raw materials - cysteine, glutamic acid and glycine. Glutathione exits primarily in its reduced form (GSH), or its oxidized disulfide (GSSH) form within the cell. Under normal and healthy conditions most of the glutathione (more than 90%) exists in reduced GSH form while very little exists in oxidized GSSH form. Higher concentrations of GSSH indicates high concentrations of free radicals and hence, increased oxidative stress in the body. Glutathione also helps remove toxins and waste products from the body. Higher levels of glutathione (GSH) indicate better health conditions and an increased ability to fight illnesses and disorders in the body. It protects eyes, liver, immune system, heart, arteries, blood vessels, lungs and even skin from damage by oxidative stress. Because of this, glutathione is known as a 'master antioxidant' or 'super antioxidant'.
Glutathione also plays a major role in maintaining overall balance in the body. It can help prevent and treat cancer, cardiac disorders, premature aging, asthma, and certain autoimmune diseases. Its anti-oxidant property helps remove free radicals, metabolic toxins, and environmental poisons from the body, enhancing overall liver metabolism and health. It is also used to treat infertility, cataracts and HIV infection. Glutathione also plays an important role in many metabolic processes like synthesis of DNA, repair of damaged DNA, amino acid transport, transport metals across membranes (necessary for the production of enzymes), protects against long-term damage caused by smoking and alcohol.
Glutathione also serves to recycle the spent (oxidized) vitamin C and vitamin E in the body. These therapeutic roles of glutathione are mainly due to the action of two enzymes - glutathione peroxidase (GPO) and glutathione-S-transferase (GST). While GPO, made up of 8 glutathione molecules held together by 4 selenium atoms and is responsible for scavenging of free radicals, GST acts similarly to GPO by eliminating toxins from the body via bile or urine.
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Glutathione was first discovered in 1888 by De Rey-Pailhade who named it as 'philothion'. However, it was only in 1921 when Sir Gowland Hopkins discovered its reducing properties, renamed it glutathione - that its potential medicinal benefits were recognized. It was initially used to treat cataracts, but it was only in late 1980s that the true multi-tissue protective nature of glutathione came to light.
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Though all the medicinally beneficial properties of glutathione are attributed to its strong antioxidant properties, low levels of glutathione have been implicated in many cellular disorders. Hence, the preventive effects of glutathione are mainly due to its normal levels in the body and any decrease in these normal levels leads to manifestation of disease.
Anti-cancer:
Glutathione levels are found to be extremely low in cancer patients. The ability of glutathione to eliminate toxic substances from the body is related to its anti-cancer effect. Specific conditions like liver cancer and liver cirrhosis are caused mainly due to depletion of glutathione in the liver. The anti-cancer effects of glutathione are also attributed to its ability to chelate (latch onto) metal ions like mercury, lead and cadmium, which have toxic effects in the body. Researchers at the Netherlands Kancer Institute at Amsterdam have suggested that 600 mg/day of N-acetylcysteine is safe and necessary for chemoprevention of lung cancer, since it enhances intracellular levels of glutathione.
Anti-HIV:
Researchers at Stanford, Harvard and many European Universities have found that glutathione has the unique ability to restore a dying immune system, as in case of HIV infections like AIDS. The immune boosting properties of glutathione are again attributed to its strong antioxidant ability. The first clinical trial conducted involved administration of 3-8 g/day of glutathione to individuals whose immune system had very low levels of specific T-cells. This treatment led to the doubling of these immune cells in just 2 years. A study led by Herzenberg at the Stanford University of Medicine, showed that HIV-infected patients, who also had low levels of glutathione, had a mortality rate of up to 80% while it was just 20% in HIV patients with normal levels of glutathione. Another study group in Italy observed that individuals who were affected with Hepatitis C and HIV had extremely low blood, liver, and lymphocyte glutathione levels when compared to individuals with just Hepatitis C infection.
Detoxification:
Owing to its very strong antioxidant properties, glutathione plays a very important role in removing toxins, posionous chemicals, and metal ions from the body. Glutathione can remove metal ions like cadmium, lead, and mercury, as well as toxic substances like epoxides and halides (chlorine, bromine, etc.) from the body. Glutathione is also believed to help the liver recover in specific cases of poisoning (e.g., over-usage of acetaminophen).
Cardiac disorders:
Glutathione also protects the arteries and blood vessels from the harmful effects of free radicals and peroxides. Individuals with cardiac disorders have been reported to contain extremely low levels of glutathione. Glutathione along with selenium (forming glutathione peroxidase), deactivates free radicals, especially toxic ones arising out of lipid peroxidation (like rancid cholesterol).
Fertility:
A study at the University of Rome has shown that administration of 600 mg/day of glutathione to infertile men, led to a positive improvement of male impotency. Such individuals exhibited increased number of functional sperm with increased motility. Glutathione is believed to restore this fertility in men by preventing the sperm membrane from damage by free radicals that are produced by lipid peroxidation.
Anti-aging:
Mitochondrial glutathione plays a very important role in slowing and delaying the process of aging. Mitochondria are the energy sources of the cell. Any damage to mitochondrial DNA is related to oxidation of glutathione. Hence, continuous supplementation of antioxidants to the mitochondria is extremely important to protect it against the long-term effect of free radicals that can lead to indicators of aging.
Prevention of cataracts:
Continuous supply of antioxidants to the retinal tissue in the eye is necessary to protect the eye tissue against oxygen-induced damage. Glutathione peroxidase is the main active enzyme in the retina and any deficiency in glutathione or selenium has been linked to the development of cataracts.
Ballatori N, Krance SM, Notenboom S, et al. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009 Jan 23.
Barbaro G, Di Lorenzo G, Soldini M, et al. Hepatic glutathione deficiency in chronic hepatitis C: quantitative evaluation in patients who are HIV positive and HIV negative and correlations with plasmatic and lymphocytic concentrations and with the activity of the liver disease. Am J Gastroenterol. 1996;91(12):2569-73.
Fraternale A, Paoletti MF, Casabianca A, et al. GSH and analogs in antiviral therapy. Mol Aspects Med. 2008 Sep 27.
Hou BS, Wang ZD, Shang XJ. Glutathione and male reproduction. Zhonghua Nan Ke Xue. 2008;14(11):1023-6.
Lenzi A, Culasso F, Gandini L, Lombardo F, Dondero F. Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. Hum Reprod. 1993;8(10):1657-62.
Marazzi G, Rosanio S, Caminiti G, et al. The role of amino acids in the modulation of cardiac metabolism during ischemia and heart failure. Curr Pharm Des. 2008;14(25):2592-604.
Sahaf B, Heydari K, HerzenbergLA, Herzenberg LA. The extracellular microenvironment plays a key role in regulating the redox status of cell surface proteins in HIV-infected subjects. Arch. Biochem. Biophys. 2005;434(1):26-32.
Sastre J, Pallardo FV, Vina J. Glutathione, oxidative stress and aging. Age. 1996;19(4):129-139.
Wang H, Gao J, Sun X, et al. The Effects of GPX-1 Knockout on Membrane Transport and Intracellular Homeostasis in the Lens. J Membr Biol. 2009;227(1):25-37.
Wu G, Fang YZ, Yang S, et al. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489-92.
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Sources and Forms of Glutathione: |
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Glutathione is rapidly synthesized by the liver, kidney and other tissues of the body from basic amino acids. However, the best sources of dietary glutathione include fresh uncooked meat, vegetables and fruits. Cooking or even pasteurization leads to degradation of natural glutathione. While asparagus has the highest content of glutathione, avocadoes, squash, cauliflower, broccoli, apples, grapefruit, spinach, walnut, garlic and tomatoes are also rich in glutathione.
Though preserving glutathione in dietary sources is difficult, eating foods that are rich in the compounds that enhance the synthesis of glutathione in the body is more beneficial than supplementing directly with glutathione. Studies have shown that eating foods rich in nutritional compounds like vitamin C, N-acetylcysteine, curcumin, glutamine, and un-denatured whey protein, is more beneficial than eating foods rich in glutathione. This is also supported by the fact that administration of 3 g/day of glutathione does not lead to any significant increase in levels of circulating glutathione in the body.
Vitamin C is one of the major metabolic stimulators of glutathione synthesis. Studies have shown that administration of just 500 mg/day of vitamin C led to an increase in glutathione levels in red blood cells by more than 50%. Un-denatured whey protein is also considered one of the best boosters of glutathione synthesis. Whey protein is rich in the amino acids glutamic acid, glycine and cysteine, which are the raw materials for glutathione. The antioxidant silymarin from the Mary Thistle herb prevents depletion of glutathione in the liver and also increases the levels of glutathione by almost 35%. Curcumin is also a potent stimulator of glutathione synthesis by the body since curcumin up-regulates the expression of genes responsible for enzymes that catabolize the synthesis of glutathione. In addition to these, vitamin B6, riboflavin, and selenium are also required for synthesis of glutathione by the body. Hence, supplementation of foods rich in these compounds is far more beneficial and effective than foods rich in glutathione, especially since glutathione levels are heavily degraded during cooking and processing of foods.
Bounous G, Gold P. The biological activity of undenatured dietary whey proteins [Immunocal]: role of glutathione. Clin Invest Med. 1991;14(4):296-309.
Dickinson DA, Iles DE, Zhang H, Blank V, Forman HJ. Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB J. 2003;17(3):473-475.
Johnston CJ, Meyer CG, Srilakshmi JC. Vitamin C elevates red blood cell glutathione in healthy adults. Am J Clin Nutr. 1993;58:103-5.
Valenzuela A, Aspillaga M, Vial S, Guerra R. Selectivity of silymarin on the increase of glutathione content in different tissues of rat. Planta Med. 1989 Oct;55(5):420-2.
Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667-9.
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Recommended Dosage of Glutathione: |
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Due to the poor absorption of glutathione from the gastrointestinal tract, glutathione supplements have little or no effect. Human gastrointestinal tracts have an enzyme (gamma-glutamyltranspeptidase) that breaks down glutathione. Hence, supplements rich in N-acetyl cysteine, vitamin C, selenium, curcumin are recommended for stimulating the synthesis of natural glutathione. Most of the glutathione supplements in the market are a combination of these nutritional compounds that boost the production of glutathione, and contain very little or no actual glutathione within them.
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Safety and Side Effects of Glutathione: |
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Since glutathione is rapidly degraded in the gastrointestinal tract, there are no known contraindications. However, taking glutathione along with anti-psychotic drugs like haloperidol and chemopreventive drugs like cisplatin is not advised since glutathione may inactivate these drugs.
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Frequently Asked Questions on Glutathione: |
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How important is glutathione for balanced health and why?
Glutathione is the best antioxidant available so far. Owing to these extensive antioxidant properties, glutathione can protect the bodily tissues from damage due to free radicals and oxidative stress. Production of free radicals and resulting oxidative stress are common metabolic byproducts that can cause severe damage to tissues. Hence, it is very important to remove these free radicals from tissues as soon as they are produced. Glutathione helps remove free radicals from tissues in liver, kidneys, retinas, heart, lungs, etc. By doing so, glutathione not only protects the tissues from damage, but also prevents metabolic imbalances that may lead to manifestation of diseases. Several reports confirm the preventive role played by glutathione in diseases like cancer, cardiac ischemia, metal toxicity, metal poisoning, cataracts, impotency, and HIV infections. Glutathione also stimulates the production of disease-fighting T-cells, thus strengthening the body's immune system.
Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009 Jan 23.
Jenner P. Oxidative damage in neurodegenerative disease. Lancet. 1994;344:796-8.
Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489-92.
Why dont I see any supplements that contain only glutathione? What should I keep in mind while taking these supplements?
Glutathione is rapidly degraded by the gastrointestinal tracts in humans. Hence, oral administration of glutathione has little value. Studies have shown that administration of up to 3 g of glutathione has no effect on physiological concentrations of glutathione in the body. Even supplementing glutathione with foods rich in this antioxidant is of no use, since glutathione is degraded even upon mild heating (cooking or pasteurization). Hence, it is advisable to consume supplements like vitamin C, selenium, curcumin and N-acetyl-cysteine that not only provide raw materials for glutathione but also stimulate the metabolic pathways responsible for production of glutathione from these raw materials.
Bounous G, Gold P. The biological activity of undenatured dietary whey proteins: role of glutathione. Clin Invest Med. 1991;14(4):296–309.
Johnston CJ, Meyer CG, Srilakshmi JC. Vitamin C elevates red blood cell glutathione in healthy adults. Am J Clin Nutr. 1993;58:103-5.
Valenzuela A, Aspillaga M, Vial S, Guerra R. Selectivity of silymarin on the increase of glutathione content in different tissues of rat. Planta Med. 1989 Oct;55(5):420-2.
Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667-9.
What can I do to stimulate my glutathione levels?
Glutathione is rapidly degraded in the human gastrointestinal tract. Hence, it better to eat foods that are rich in compounds like vitamin C, curcumin and selenium that stimulate synthesis and production of glutathione within the body. Whey protein also aids in glutathione synthesis in the body since it is rich in the raw materials-glycine, cysteine, and glutamate that are required for synthesis of glutathione. Some of the foods that stimulate glutathione synthesis in the body include berries, citrus fruits, peppers, nuts, meat, turmeric spice, and also whey protein. In addition, supplementation with vitamin C, selenium, curcumin and N-acetylcysteine also helps boost glutathione synthesis in the body.
Bounous G, Gold P. The biological activity of undenatured dietary whey proteins: role of glutathione. Clin Invest Med. 1991;14(4):296–309.
Micke P, Beeh DM, Schlaak JF, Buhl R. Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients. Eur J Clin Invest. 2001;31(2):171–8.
Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667–9.
Is glutathione the miracle cure for all diseases?
Though glutathione does not seem to have the ability to cure all diseases, it definitely seems to have the ability to prevent the onset of many diseases. Since glutathione is a very potent antioxidant and found in almost all tissues of the body, normal levels of glutathione have been able to partly restore health in those with diseases like cancer and heart disorders.
How important is glutathione for detoxifying the body?
Glutathione is an important part of liver function. The liver separates the substances that can be absorbed by the body from the substances that need to be eliminated from the body, and much of the body’s detoxifying process occurs through the liver. Hence, the liver is more prone to attack by free radicals more than other tissues. The sulfur in glutathione (that comes from cysteine) is responsible for the chelating property of glutathione – allowing it to bind to many toxic chemicals (such as mercury, lead, cadmium, chlorides, bromides, etc) that are produced by the liver metabolic processes – which then leads to elimination of these toxins through urine.
Lund ME, Banner W, Clarkson TW, Berlin M. Treatment of acute methylmercury ingestion by hemodialysis with N-acetylcysteine. Toxicol Clin Toxicol. 1984;22:31-49.
Zalups RK, Lash LH. (1996). Interactions between glutathione and mercury in the kidney, liver and blood. In: Chang, LW, ed. Toxicology of Metals. Boca Raton: CRC Press. ppg 145-63.
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Additional Research on Glutathione: |
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Glutathione and Detoxification
Kabler SL, Seidel A, Jacob J, Doehmer J, Morrow CS, Townsend AJ. Differential protection by human glutathione S-transferase P1 against cytotoxicity of
benzo[a]pyrene, dibenzo[a,l]pyrene, or their dihydrodiol metabolites, in bi-transgenic cell lines that co-express rat versus human cytochrome P4501A1.
Chem Biol Interact. 2009 May 15;179(2-3):240-6.
Prévéral S, Gayet L, Moldes C, Hoffmann J, Mounicou S, Gruet A, Reynaud F, Lobinski R, Verbavatz JM, Vavasseur A, Forestier C. A common highly
conserved cadmium detoxification mechanism from bacteria to humans: heavy metal tolerance conferred by the ATP-binding cassette (ABC) transporter
SpHMT1 requires glutathione but not metal-chelating phytochelatin peptides. J Biol Chem. 2009 Feb 20;284(8):4936-43.
Glutathione and Cancer
Ilonen IK, Rasanen JV, Sihvo EI, Knuuttila A, Salmenkivi KM, Ahotupa MO, Kinnula VL, Salo JA. Oxidative stress in non-small cell lung cancer: Role of
nicotinamide adenine dinucleotide phosphate oxidase and glutathione. Acta Oncol. 2009 Mar 23:1-8.
Kalikaki A, Kanaki M, Vassalou H, Souglakos J, Voutsina A, Georgoulias V, Mavroudis D. DNA repair gene polymorphisms predict favorable clinical
outcome in advanced non-small-cell lung cancer. Clin Lung Cancer. 2009 Mar;10(2):118-23.
Odom RY, Dansby MY, Rollins-Hairston AM, Jackson KM, Kirlin WG. Phytochemical induction of cell cycle arrest by glutathione oxidation and reversal by
N-acetylcysteine in human colon carcinoma cells. Nutr Cancer. 2009;61(3):332-9.
Sampaio AC, Morari EC, Bufalo NE, Leite JL, Lima CS, Ward LS. Lack of influence of glutathione S-transferase genotype profile on cancer susceptibility in
smokers and nonsmokers. Med Sci Monit. 2009 Jan;15(1):CR10-5.
Glutathione and Fertility
Hou BS, Wang ZD, Shang XJ. Glutathione and male reproduction. Zhonghua Nan Ke Xue. 2008 Nov;14(11):1023-6.
Stradaioli G, Sylla L, Monaci M, Maiorino M. Phospholipid hydroperoxide glutathione peroxidase in bull spermatozoa provides a unique marker in the
quest for semen quality analysis. Theriogenology. 2009 Apr 2.
Glutathione and Anti-Aging
Ha EJ, Smith AM. Selenium-dependent Glutathione Peroxidase Activity is Increased in Healthy Post-menopausal Women. Biol Trace Elem Res. 2009 Feb
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