Tuesday, April 22, 2008

Glutathione - The Master Antioxidant or Acid Buster

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 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 alkaline 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, factors which are involved in the detoxification of xenobiotics, including carcinogenic genotoxicants, and for the glutathione peroxidases, crucial selenium-containing antioxidant factors.

It is also involved in the regeneration of ascorbate from its oxidized form, dehydroascorbate.

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.

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 factor gamma-glutamylcysteine synthetase -- the rate limiting step -- and second, glycine is added to the C-terminal of gamma-glutamylcysteine via the factor 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 glutathione disulfide reductase is the principal molecule that maintains glutathione in its reduced form. This latter molecule uses as its cofactor NADPH (reduced nicotinamide adenine dinucleotide phosphate). NADPH is generated by the oxidative reaction in the pentose phosphate pathway.

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 (Co-factor Q-1) 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 (red blood cells) 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 dis-ease, probably accelerated pathogenesis of the dis-ease.

Acute manifestations of functional glutathione deficiency can be seen in those who have taken an overdosage of acetaminophen (aspirin). This results in depletion of glutathione in the hepatocytes, leading to liver failure and death, if not promptly treated.

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 many 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.

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.

Many of the marketed glutathione dietary supplement products are obtained from yeast fermentation, as is the orphan drug. This is not the case with Dr.
Robert O. Young's, Young pHorever Glutathione which is a glutathione extract from avocados.

www.phmiracleliving.com

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.

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 to help maintain the alkaline design of the cell.

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, which are major antioxidants. These antioxidants 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 factors 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 factors 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.

The pharmacokinetics of oral glutathionine in humans are not well understood. It appears that in some animals (mice, rats, guinea pigs), serum glutathione levels do increase following its oral administration.

Though glutathione is undoubtedly a potent antioxidant.
There is preliminary evidence that it might eventually prove to be useful in the management of some cancers, atherosclerosis, diabetes, lung disorders, noise-induced hearing loss, male infertility and to help prevent or ameliorate various toxicities.

It may also have some anti-viral (acid) activity.
Glutathione is an orphan drug for the treatment of AIDS-associated cachexia.

RESEARCH SUMMARY

The use of glutathione in cancer treatment has been two-fold. It has been investigated as an antitumor agent in its own right and as a chemoprotectant used to diminish the toxicities of some cancer drugs.

In one animal study, glutathione produced significant regression of aflatoxin-induced liver cancers and significantly enhanced survival.

All rats exposed to aflatoxin but not given glutathione died within 24 months of exposure to the carcinogen, but 81% of the glutathione-treated animals were still alive at the end of the 24 months. The researchers concluded that the glutathione-effect noted in this study "strongly suggests that this antioxidant merits further investigation as a potential antitumor agent in humans."

Human cancer studies, so far, have utilized glutathione in a secondary role--principally to protect against the toxicity of cisplatin.
Its role in this regard has been found effective in several studies wherein it has been demonstrated to diminish cisplatin-induced nephrotoxicity and neurotoxicity.

Early research indicates that exogenous glutathione may significantly inhibit platelet aggregation and improve other hemostatic and hemorheological factors in atherosclerotic patients. In other preliminary clinical work, glutathione has been found to help preserve renal function in patients who had coronary artery bypass operations.

A glutathione nasal preparations has been helpful in reversing the oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis, and it has helped suppress lung epithelial surface inflammatory cell-derived oxidants in patients with cystic fibrosis.

Similar nebulizing treatment has been given to HIV patients to augment deficient glutathione levels of the lower respiratory tract with the idea of improving host defense in these immuno-compromised individuals.

Glutathione has also been shown to enhance insulin secretion in elderly subjects with impaired glucose tolerance. There are some further preliminary indications that glutathione might be helpful in some with diabetes, but more research is needed before any meaningful conclusions can be made.

In a double-blind, placebo-controlled study, injected glutathione demonstrated a significant positive effects on sperm motility and morphology in infertile men. And, finally, in another study that needs followup, glutathione exhibited significant in vitro inhibition of herpes simplex virus type 1 replication. It appears that the mechanism of this effect is due to glutathione's redox-modulating active. Some viral (acidic) outfections, including HIV outfection, result in oxidative stress which may be a major mechanism of their pathogenesis, modulating oxidative stress could be an antiviral (antiacid) maneuver.

Glutathione is an orphan drug for the treatment of AIDS-associated cachexia.

Oral doses of up to 2000 milligrams daily are well tolerated. There are no reports of adverse reactions.

INTERACTIONS DRUGS

Cisplatin (Chemothearpy drug): Glutathione, administered parenterally, may ameliorate some of the adverse reactions of cisplatin.

OVERDOSAGE

There have been no reports of glutathione overdosage in the literature.

DOSAGE AND ADMINISTRATION

Glutathione is available as a single ingredient dietary supplement. Dosage ranges from 50 to 2000 milligrams daily. One teaspoon per Young pHorever Liquid Glutathione equals 430 milligrams.

HOW SUPPLIED

Liquid - one teaspoon of Young pHorever
Glutathione equals 430 milligrams.

SHOULD I ADD LIQUID GLUTATHIONE TO MY DIET?

Yes, as a major protectant from
dietary and lifestyle acidity.

LITERATURE

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Lash LH, Hagen TM, Jones DP. Exogenous
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Lenzi A, Culasso F, Gandini L, et al.
Placebo-controlled, double-blind,
cross-over trial of glutathione therapy in male infertility. Hum Reprod. 1993; 8:1657-1662.

Lenzi A, Picardo M, Gandini L, et al.
Glutathione treatment of dyspermia:
effect on the lipoperoxidation process.
Hum Reprod. 1994; 9:2044-2050.

Loguercio C, Di Pierro M. The role of
glutathione in the gastrointestinal
tract: a review. Ital J Gastroenterol
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Blood glutathione synthesis rates in
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Proc Natl Acad Sci USA. 1990; 87:1715-1719.

Meister A. On the antioxidant effects of ascorbic acid and glutathionine. Biochem Pharmacol. 1992; 44:1905-1915.

Murphy ME, Scholich H, Sies H. Protection by glutathione and other thiol compounds against the loss of protein thiols and tocopherol homologs during microsomal lipid peroxidation. Eur J Biochem. 1992; 210:139-146.

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Rathbun WB. Augmentation of human and
rat lenticular glutathione in vitro by
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J Med Chem. 1996; 39:1676-1681.

Novi AM. Regression of aflatoxin B1-induced hepatocellular carcinomas by reduced glutathione. Science. 1981; 212:541-542.

Ohinataab Y, Yamasobac T, Schachta J,
Millera JM. Glutathione limits noise-induced hearing loss. Hear Res. 2000; 146:28-34.

Palamara AT, Perno C-F, Ciriolo MR, et al.
Evidence for antiviral activity of glutathione:
in vitro inhibition of herpes simplex virus type
1 replication. Antiviral Res. 1995; 27:237-253.

Paolisso G, Giugliano D, Pizza G, et al.
Glutathione infusion potentiates glucose-induced insulin secretion in aged patients with impaired glucose tolerance. Diabetes Care.
1992; 15:1-7.

Roum JH, Borok Z, McElvaney NG, et al.
Glutathione aerosol suppresses lung
epithelial surface inflammatory cell-derived oxidants in cystic fibrosis. J Appl Physiol.
1999; 87:438-443.

Samiec PS, Drews-Botsch C, Flagg EW, et al.
Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radic Biol Med. 1998; 24:699-704.

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Shaw CA, ed. Glutathione in the Nervous System. London: Taylor and Francis; 1998.

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