Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver.

As a normal attribute of aerobic life, structural damage to organic compounds of a wide variety (DNA, proteins, carbohydrates and lipids) may occur as a consequence of oxidative reactions. Oxidative damage inflicted by reactive oxygen species has been called “oxidative stress”. Biological systems contain powerful enzymatic and nonenzymatic antioxidant systems, and oxidative stress denotes a shift in the prooxidant/antioxidant balance in favor of the former. Diverse biological processes such as inflammation, carcinogenesis, ageing, radiation damage and photobiological effects appear to involve reactive oxygen species. This field of research provides new perspectives in biochemical pharmacology, toxicology, radiation biochemistry as well as pathophysiology.

Biochemistry of Oxidative Stress

Publisher Summary This chapter discusses the role of glutathione (GSH) and glutathione s-transferases in metabolism of chemical carcinogens and other electrophilic agents. GSH is a tripeptide (I) that is present in nearly all living cells and is the most abundant sulfhydryl compound present in animal tissues, mainly in the cytosol. The chapter illustrates the wide range of electrophilic agents, including several known mutagens and carcinogens, which conjugate with GSH, a process usually catalyzed by the GSH S-transferases. This conjugation is probably a protective mechanism and is the initial stage in mercapturic acid biosynthesis for the elimination of foreign compounds from the body. GSH S-transferases provide protection not only by catalyzing the conjugation of a potential toxicant with GSH, but also by preferentially binding, even covalently, that toxicant. The reactive electrophiles that conjugate with GSH also bind to DNA, RNA, and protein and identification of GSH conjugates provide information on the nature of these biologically active intermediates or even their immediate precursors. Thus, the knowledge of the way in which mutagens and carcinogens are metabolized is essential to a better understanding of their mode of action and of the processes for their detoxication.

The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents.

Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes.

Glutathione as reduced glutathione (GSH) and as the disulfide (GSSG) is a unique peptide that continues to interest toxicologists-as reflected in the numerous symposia and reviews ( 1-6). This article undertakes to describe the role of mitochondrial glutathione in cellular response to toxic exposures that include loss of the homeostases of Ca2+ and protein thiols. Because of the numerous reviews on the glutathione S-transferases (7-10), only the per­ oxidase activity of membrane-associated glutathione S-transferases is dis­ cussed. Mammalian cells have evolved protective mechanisms to minimize in­ jurious events that result from toxic chemicals and normal oxidative products of cellular metabolism. A major endogenous protective system is the glu­ tathione redox cycle (2). Glutathione is present in high concentrations as GSH in most mammalian cells (generally in the millimolar range), with minor fractions being GSSG, mixed disulfides of GSH and other cellular thiols, and minor amounts of thioethers ( 1) . GSH acts both as a nucleophilic "scavenger" of numerous compounds and their metabolites, via enzymatic and chemical mechanisms, converting electrophilic centers to thioether bonds, and as a substrate in the GSH peroxidase-mediated destruction of hydroperoxides. GSH depletion to about 20-30% of total glutathione levels can impair the cell's defense against the toxic actions of such compounds and may lead to cell injury and death (3, 1 1) .

J.R. Prohaska

Papers

Glutathione peroxidase activity of glutathione-s-transferases purified from rat liver.

Glutathione peroxidase: inhibition by cyanide and release of selenium