Cellular and clinical implications of glutathione

Glutathione (␥-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, ␥-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by ␥-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-acetylcysteine, 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. J. Nutr. 134: 489 -492, 2004.

The tripeptide thiol glutathione (GSH) has facile electron-donating capacity, linked to its sulfhydryl (—SH) group. Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes; it provides protection also for the mitochondria against endogenous oxygen radicals. Its high electron-donating capacity combined with its high intracellular concentration endows GSH with great reducing power, which is used to regulate a complex thiol-exchange system (—SH —S-S—). This functions at all levels of cell activity, from the relatively simple (circulating cysteine/— SH thiols, ascorbate, other small molecules) to the most complex (cellular —SH proteins). Glutathione is homeostatically controlled, both inside the cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it as per the gamma-glutamyl cycle. Glutathione is most concentrated in the liver (10 mM), where the " P450 Phase II " enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates, in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of —SH/reducing power. GSH depletion leads to cell death, and has been documented in many degenerative conditions. Mitochondrial GSH depletion may be the ultimate factor determining vulnerability to oxidant attack. Oral ascorbate helps conserve GSH; cysteine is not a safe oral supplement, and of all the oral GSH precursors probably the least flawed and most cost-effective is NAC (N-acetylcysteine). (Alt Med Rev 1997; 2(3):155-176) Glutathione (γ-glutamylcysteinylglycine, GSH) is a sulfhydryl (—SH) antioxidant, an-titoxin, and enzyme cofactor. Glutathione is ubiquitous in animals, plants, and microorganisms, and being water soluble is found mainly in the cell cytosol and other aqueous phases of the living system. 1-4 Glutathione often attains millimolar levels inside cells, which makes it one of the most highly concentrated intracellular antioxidants. Glutathione exists in two forms (Fig. 1): The antioxidant " reduced glutathione " tripep-tide is conventionally called glutathione and abbreviated GSH; the oxidized form is a sulfur-sulfur linked compound, known as glutathione disulfide or GSSG. The GSSG/GSH ratio may be a sensitive indicator of oxidative stress.

Drug Design Reviews - Online, 2005

Thiol-containing compounds are central actors in many biochemical and pharmacological reactions. The response of cells to any stress (including cell division and apoptosis) involves changes in thiol content as they are consumed to protect cells via different actions (direct modification/regulation of biomolecules, antioxidativity, detoxification, signal transmission). The story of glutathione, the basic intracellular thiol-containing compound, ranges throughout different scientific fields. The importance of this biomolecule is highly impressive. Reduced glutathione (GSH) is a principal actor in many physiological and pharmacological reactions. There are about 60 000 entries under "glutathione" found in the Medline database. The aim of this short review is to characterize glutathione and show that due to an intriguing and multifaceted biofunctionality in the human body this tripeptide itself, as well as its analogues, belongs to the group of molecules looking for broad clinical use (besides being excellent antioxidants). This information might draw more attention to the discovery and investigation of glutathione system supporting/relating substances with a substantial clinical impact.

Free Radical Biology and Medicine, 1999

Glutathione (GSH) is the major cellular thiol participating in cellular redox reactions and thioether formation. This article serves as introduction to the FRBM Forum on glutathione and emphasizes cellular functions: What is GSH? Where does it come from? Where does it go? What does it do? What is new and noteworthy? Research tools, historical remarks, and links to current trends.

Nutrition, 2002

GSH is quantitatively the most import biological antioxidant and scavenger. In addition it has a number of important functions in amino acid transport across membranes, in protein synthesis and degradation, in gene regulation and in cellular redox regulation. It becomes

Nutrition, 2001

GSH is quantitatively the most import biological antioxidant and scavenger. In addition it has a number of important functions in amino acid transport across membranes, in protein synthesis and degradation, in gene regulation and in cellular redox regulation. It becomes

Nutrition, 2001

GSH is quantitatively the most import biological antioxidant and scavenger. In addition it has a number of important functions in amino acid transport across membranes, in protein synthesis and degradation, in gene regulation and in cellular redox regulation. It becomes

Nutrition, 2001

GSH is quantitatively the most import biological antioxidant and scavenger. In addition it has a number of important functions in amino acid transport across membranes, in protein synthesis and degradation, in gene regulation and in cellular redox regulation. It becomes

2011

All organisms require an equivalent source for living. Reduced glutathione is the most abundant thiol containing protein in mammalian cells and organs. Glutathione was discovered by Hopkins in 1924 who published his findings in JBC. It is a three peptide containing glutamic acid, cystein and glycin and is found in reduced and oxide forms in cell. High concentration of glutathione and its high reduced/oxide potential makes GSH a powerful antioxidant and the first defense line against free radicals. However, glutathione is the most efficient tool for detoxification of xenobiotic. In several studies, the effect of GSH on different cell types has been investigated and so, in this study, a review of the glutathione function, focusing on cell proliferation and differentiation would be carried out.