INHIBITION OF GLUTATHIONE-RELATED ENZYMES AND CYTOTOXICITY OF ETHACRYNIC-ACID AND CYCLOSPORINE

Glutathione (GSH) is an endogenous thiol that detoxifies active oxygen and reactive species formed during intermediary metabolism and drug d etoxification. Compounds with a range of potential toxicities were tes ted for their abilities to affect GSH reductase and GSH S-transferase activities, which are each components of the two principal detoxificat ion pathways in which GSH participates. A high performance liquid chro matographic method for determining oxidized and reduced GSH was modifi ed to assay GSH reductase activity. With this method it was possible t o demonstrate that ethacrynic acid, which inhibits GSH S-transferase, also inhibits the activity of GSH reductase. Inhibition of GSH reducta se by ethacrynic acid was similar to that seen with carmustine (BCNU). GSH reductase activity was not affected by cis- or transplatin, buthi onine sulfoximine, other loop diuretics, cyclosporine A or aminoglycos ides. Cyclosporine inhibited GSH S-transferase at 50 mu M and higher c oncentrations. These results support a role for GSH-mediated detoxific ation mechanisms in ethacrynic acid- and cyclosporine-associated cytot oxicity, which may mediate their toxicities and their potential as adj unctive agents in antineoplastic therapy. A better understanding of th e mechanism of their toxicity can greatly extend the clinical usefulne ss of these agents, as this toxicity is the basis of both their therap eutic and antitherapeutic actions.