Glutathione metabolism and its selective modification.

Glutathione (y-Glu-CysH-Gly) (GSH)' is widely distributed in animal tissues, plants, and microorganisms.' It is typically present in high (0.1-10 mM) levels and is thus both the most prevalent cellular thiol and the most abundant low molecular weight peptide. In many cells GSH accounts for more than 90% of the total nonprotein sulfur. GSH was recognized 100 years ago, and its structure was established in 1935 (2). Thousands of papers on GSH have appeared? The two characteristic structural features of GSH (y-Glu linkage, "SH) promote its intracellular stability4 and are intimately associated with its functions. GSH has been adapted through evolution to perform many diverse functions. GSH protects cells from the toxic effects of reactive oxygen compounds and is an important component of the system that uses reduced pyridine nucleotide to provide the cell with its reducing properties; these promote, for example, intracellular formation of cysteine (from cystine) and the thiol forms of proteins. GSH functions in catalysis, metabolism, and transport; it participates in reactions involving the synthesis of proteins and nucleic acids and in those that detoxify free radicals and peroxides. GSH forms conjugates with a variety of compounds of endogenous and exogenous origin and is a cofactor for various enzymes (Fig. 1, legend). The intracellular level of GSH is much greater than that of cysteine; GSH serves as a storage and transport form of cysteine moieties. GSH is synthesized intracellularly and is exported from cells; its breakdown is initiated by y-glutamyl transpeptidase, an enzyme attached to the external surface of certain cell membranes. Export of GSH functions in interorgan and intraorgan transfer of cysteine moieties, in the protection of cell membranes, and as part of a pathway of transport for cyst(e)ine and probably other amino acids. Biochemical studies have elucidated the enzymatic bases of the functions of GSH. Of major importance has been the development of selective enzyme inhibitors which are potential therapeutic agents. It is now possible to increase or to decrease cellular GSH levels and also to selectively inhibit reactions involved in GSH metabolism. Such modulation of GSH metabolism has therapeutic promise in the selective destruction of cells and in their protection. There is currently interest in modulation of GSH levels during chemotherapy and radiotherapy of tumors, including tumors that exhibit "multi-drug" resistance. Methods for increasing cellular levels of GSH have been developed; increased cellular levels protect cells against oxidative damage, toxic compounds, and radiation.