The fall and rise of cellular glutathione levels: enzyme-based approaches

Present knowledge of the pathways of metabolism and transport of glutathione and of its functions has been substantially advanced by study of the enzymes involved in glutathione metabolism, especially by investigations that have elucidated their mechanisms of action, active site topology, and other aspects of their behavior. Such information has made it possible to design selective enzyme inhibitors, which have served as valuable experimental tools and which may also be useful in therapy. Cellular glutathione levels may be lowered or raised by appropriate biochemical procedures. Glutathione synthesis is effectively blocked by administration of buthionine sulfoximine, which selectively binds to the active site of gamma-glutamylcysteine synthetase. Cellular levels of glutathione may be increased by administration of cysteine precursors such as L-2-oxothiazolidine-4-carboxylate, which is effectively transported into cells and converted by 5-oxoprolinase to cysteine, which is utilized for glutathione synthesis. Administration of gamma-glutamylcysteine, gamma-glutamylcysteine disulfide, or gamma-glutamylcysteine also leads to increased cellular levels of glutathione, especially in the kidney. These gamma-glutamyl amino acids are transported and provide substrate for glutathione synthesis. Another way of increasing cellular glutathione levels consists of administration of glutathione esters. For example, the ester of glutathione in which the glycine carboxyl group is esterified with ethanol is well transported, and is converted to glutathione intracellularly. These studies indicate that manipulation of the cellular levels of glutathione can be achieved, and may be of value in the selective destruction of cells, and in their protection.