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Article: Nutrional Pharmacology of Glutathione - by Prof Abdulrahim Abu Jayyab,Ph.D |
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The term glutathione is typically used as a collective
term to refer to the tripeptide L-gamma-glutamyl-L-cysteinylglycine in both
its reduced and dimeric forms. Monomeric glutathione is also known as
reduced glutathione and its dimer is also known as oxidized glutathione,
glutathione disulfide and diglutathione. In this monograph, reduced
glutathione will be called glutathione— this is its common usage by
biochemists—and the glutathione dimer will be referred to as glutathione
disulfide. Glutathione is widely found in all forms of life and plays an essential role in the health of organisms, particularly aerobic organisms. In animals, including humans, and in plants, glutathione is the predominant non-protein thiol and functions as a redox buffer, keeping with its own SH groups those of proteins in a reduced condition, among other antioxidant activities. Glutathione has the following structural formula: Glutathione Glutathione (reduced) is known chemically as N-(N-L-gamma-glutamyl-L-cysteinyl)glycine and is abbreviated as GSH. Its molecular formula is C10H17N3O6S and its molecular weight is 307.33 daltons. Glutathione disulfide is also known as L-gamma-glutamyl-L-cysteinyl-glycine disulfide and is abbreviated as GSSG. Its molecular formula is C20H32N6O12S2. Glutathione is present in tissues in concentrations as high as one millimolar. Cysteine, the business residue of glutathione, neither has the solubility nor activity of glutathione at physiological pH. It appears that nature has built the cysteine molecule into the glutathione tripeptide to make the amino acid more soluble and allow it to have redox buffering activity in a living tissue environment. Glutathione also plays roles in catalysis, metabolism, signal transduction, gene expression and apoptosis. It is a cofactor for glutathione S-transferases, enzymes which are involved in the detoxification of xenobiotics, including carcinogenic genotoxicants, and for the glutathione peroxidases, crucial selenium-containing antioxidant enzymes (see Selenium). It is also involved in the regeneration of ascorbate from its oxidized form, dehydroascorbate (see Vitamin C). There are undoubtedly roles of glutathione that are still to be discovered. Glutathione is present in the diet in amounts usually less than 100 milligrams daily, and it does not appear that much of the oral intake is absorbed from the intestine into the blood (see Pharmacokinetics). Glutathione is not an essential nutrient since it can be synthesized from the amino acids L-cysteine, L-glutamate and glycine. It is synthesized in two ATP-dependent steps: first, gamma-glutamylcysteine is synthesized from L-glutamate and cysteine via the enzyme gamma-glutamylcysteine synthetase—the rate limiting step— and second, glycine is added to the C-terminal of gamma-glutamylcysteine via the enzyme glutathione synthetase. The liver is the principal site of glutathione synthesis. In healthy tissue, more than 90% of the total glutathione pool is in the reduced form and less than 10% exists in the disulfide form. The enzyme glutathione disulfide reductase is the principal enzyme that maintains glutathione in its reduced form. This latter enzyme uses as its cofactor NADPH (reduced nicotinamide adenine dinucleotide phosphate). NADPH is generated by the oxidative reaction in the pentose phosphate pathway. ACT IONS AND PHARMACOLOGY ACTIONS Glutathione has antioxidant activity. It may have detoxification, and immunomodulatory activities, and may have beneficial effects on sperm motility and in the protection against noise-induced hearing loss. It is a powerful antioxidant and detoxifies the harmful compounds in the liver, where it is then excreted through the bile. The liver also excretes glutathione directly into the bloodstream where it is used to help maintain the integrity of red blood cells, as well as protecting white blood cells. Glutathione is also found in the lungs and intestinal tract where it assists in carbohydrate metabolism as well as breaking down oxidized fats. It is also used to prevent oxidative stress in most cells and helps to trap free radicals that can damage DNA and RNA. GSH also plays major roles in drug metabolism, calcium metabolism, the gamma-glutamyl cycle, blood platelet and membrane functions. MECHANISM OF ACTION Glutathione is the principal intracellular non protein thiol and plays a major role in the maintenance of the intracellular redox state. It may be thought of as an intracellular redox buffer. Glutathione is a nucleophilic scavenger and an electron donor via the sulfhydryl group of its business residue, cysteine. Its reducing ability maintains molecules such as ascorbate and proteins in their reduced state. Glutathione is also the cofactor for the selenium-containing glutathione peroxidases (see Selenium), which are major antioxidant enzymes. These enzymes detoxify peroxides, such as hydrogen peroxide and other peroxides. Another antioxidant activity of glutathione is the maintenance of the antioxidant/reducing agent ascorbate in its reduced state. This is accomplished via glutathione-dependent dehydroascorbate reductase which is comprised of glutaredoxin and protein isomerase reductase. Glutathione may also react with the reactive nitrogen species peroxynitrite to form S-nitrosoglutathione. Glutathione S-transferases (GSTs) consist of a family of multifunctional enzymes that metabolize a wide variety of electrophilic compounds via glutathione conjunction. GSTs are involved in the detoxification of xenobiotic compounds and in the protection against such degenerative diseases as cancer. The mechanism of these enzymes involves a nucleophilic attack by glutathione on an electrophilic substrate. The resulting glutathione conjugates that form are more soluble than the original substrates and thus more easily exported from the cell. The release of glutathione-S-conjugates from cells is an ATP-dependent process mediated by membrane glycoproteins belonging to the multidrug-resistance protein (MRP) family. Proteins of the MRP family are essential for the transport of glutathione S-conjugates into the extracellular space. They are also known as glutathionine-S-conjugate pumps. Absorption of orally administered glutathione has been observed in some animals (mice, rats, guinea pigs). Oral glutathione has been demonstrated to reverse age-associated decline in immune responsiveness in mice. In one study, glutathione was found to enhance T-cell mediated responsiveness, including delayed-type hypersensitivity (DTH). The mechanism of this effect was ascribed to the antioxidant activity of glutathione. Parenterally administered glutathione was found to improve sperm motility in a small human trial. Again, the effect was thought to be due to the antioxidant activity of this substance. Noise-induced hearing loss is thought to be due to oxidative stress. Intraperitoneal administration of glutathione to guinea pigs was found to protect against noise-induced hearing loss and once more, the antioxidant activity of glutathione was thought to account for this effect. Glutathione is actually a tripeptide made up the amino acids gamma-glutamic acid, cysteine, and glycine. The primary biological function of glutathione is to act as a non-enzymatic reducing agent to help keep cysteine thiol side chains in a reduced state on the surface of proteins. Glutathione is also used to prevent oxidative stress in most cells and helps to trap free radicals that can damage DNA and RNA. There is a direct correlation with the speed of aging and the reduction of glutathione concentrations in intracellular fluids. As individuals grow older, glutathione levels drop, and the ability to detoxify free radicals decreases. Deficiency of glutathione A deficiency of gluthione is first noticed in the nervous system with a lack of co-ordination, tremors, mental disorders, and body balance, all caused by lesions in the brain. The consequences of a functional glutathione deficiency, which results in tissue oxidative stress, can be seen in some pathological conditions. For example, those with glucose 6-phosphate dehydrogenase deficiency produce lower amounts of NADPH and hence, lower amounts of reduced glutathione. This condition is characterized by a hemolytic anemia. Conditions causing chronic glutathione deficiency all result in hemolytic anemia, among other pathological consequences. Oxidative stress caused by glutathione deficiency results in fragile erythrocyte membranes. Malaria-causing organisms (Plasmodia species) do not like to feed on these sick erythrocytes. That is about the only good news regarding this situation. Chronic functional glutathione deficiency is also associated with immune disorders, an increased incidence of malignancies, and in the case of HIV disease, probably accelerated pathogenesis of the disease. Acute manifestations of functional glutathione deficiency can be seen in those who have taken an overdosage of acetaminophen. This results in depletion of glutathione in the hepatocytes, leading to liver failure and death, if not promptly treated. In conclusion Glutathione is a significant component of the collective antioxidant defenses, and a highly potent antioxidant and antitoxin in its own right. The -SH group of GSH is important for many facets of cell function, and early suggestions that GSH plays multiple regulatory roles at the cell level1 are borne out by the cumulative findings. Observations from hereditary GSH synthesis deficiencies confirm that GSH is essential both to the functionality and to the structural integrity of the cells, the tissues, and the organ systems. The glutathione status of a cell (that is, the excess of reduced over oxidized glutathione) will perhaps turn out to be the most accurate single indicator of the health of the cell. That is, as glutathione levels go, so will go the fortunes of the cell. The mitochondria may be the Achilles Heel of the aerobic cell, and mitochondrial breakdown could be the common etiologic thread in most (if not all) GSH deficiency states. The mitochondria are exposed to oxygen free radicals produced by the OxPhos processes, yet cannot make their own GSH for protection - they must expend energy to import it from the surrounding cellular cytosol. The mitochondria do have antioxidant protective enzymes that are inducable (including superoxide dismutase and catalase, but GSH peroxidase demands GSH as cofactor), but this adaptive capacity has its limits. Healthy mitochondria avidly conserve their GSH, but as cytosolic GSH levels decrease, mitochondrial GSH can fall below a critical threshold. The turning point is when, in the face of sustained oxidative challenge, the mitochondrial GSH becomes depleted. The membrane-associated enzymes that transport GSH into the mitochondria then sustain damage, and GSH import is dealt a fatal blow. As a consequence, the mitochondria become casualties of their own making, i.e., destroyed by their own endogenously-generated free radicals. The consistent findings of GSH depletion in many preclinical and clinical degenerative conditions beg the question of whether antioxidants should be universally employed - whether singly or in combination - in efforts to ameliorate functional degeneration and improve quality of life. Combinations of antioxidants given as dietary supplements seem to offer the most promise for achieving clinical breakthroughs. At times, the administration of massive amounts of ascorbate (orally or intravenously) or of sulfhydryls (GSH and NAC orally and intravenously) will be lifesaving. Prenatal diagnosis of inherited GSH abnormalities may not be far off.11 In the meantime, dietary repletion of systemic GSH holds promise for the management of conditions as diverse as Alzheimer's Disease, atherosclerotic vascular degeneration, cataract, lung insufficiencies, Parkinson's Disease, and many others. Assiduous attention to repletion of GSH also should help assist the body to manage bouts of heavy exercise or combat a chronic viral load. Particularly when employed in conjunction with ascorbate, other antioxidants, and other nutritional factors, the reducing power of GSH is a powerful orthomolecular tool for quality and length of life. Glutathione is an orphan drug for the treatment of AIDS-associated cachexia. It is thought that this disorder is due, in part, to oxidatively-stressed and damaged enterocytes. There is some evidence that although orally administered glutathione may not be absorbed into the blood from the small intestine to any significant extent, that it may be absorbed into the enterocytes where it may help repair damaged cells. Glutathione in one form or another is the subject of some medicinal chemistry research and some clinical trials. For example, an aerosolized form of glutathione is being studied in AIDS and cystic fibrosis patients. Glutathione, the principal antioxidant of the deep lung, appears to be diminished in those with AIDS. Prodrugs of gamma-L-glutamyl-L-cysteine are being evaluated as anticataract agents.The marketed glutathione dietary supplement products are obtained from yeast fermentation, as is the orphan drug. L-Cysteine and N-acetylcysteine are precursors of glutathione and are also available as dietary supplements (see L-Cysteine and N-Acetylcystein |
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