DIFFERENTIAL-EFFECTS OF CISPLATIN ON THE PRODUCTION OF NADH-DEPENDENTSUPEROXIDE AND THE ACTIVITY OF ANTIOXIDANT ENZYMES IN RAT RENAL CORTICAL SLICES IN-VITRO

Cisplatin-induced cytotoxicity has been investigated with rat renal co rtical slices in vitro. Incubation of renal slices with cisplatin caus ed an unexpected decrease in NADH-dependent, lucigenin-enhanced chemil uminescence in the homogenate of the slices in a time- and concentrati on-dependent fashion. Cisplatin caused a concentration-related (0.2-1 mM) decrease in the formation of NADH-dependent superoxide anion. Cisp latin (2 mM) significantly suppressed the chemiluminescence to 70% of control as early as 15 min. and to 15% after 90 min. of incubation. A decrease was also observed 90 min. after incubation of dices with 0.25 mM cisplatin. In addition, the activities of superoxide dismutase (SO D) and catalase in the slices were significantly increased after 60 mi n. of exposure to cisplatin (2 mM) while decreases in the activities o f glutathione (GSH) peroxidase and GSSG reductase became significant a t 90 and 120 min. of incubation respectively. SOD and catalase activit ies were increased by 1.6 and 1.5 fold respectively after 90 min. of i ncubation and the activities of GSH peroxidase and GSSG reductase were decreased to 82% and 72% of control, respectively at 120 min. Both di thiothreitol (2 mM), a sulphydryl agent and diphenylphenylenediamine ( 5 mu M), an antioxidant, protected against cisplatin-induced leakage o f lactate dehydrogenase, lipid peroxidation and decreases of GSH perox idase and GSSG reductase but had no effect on the decrease of chemilum inescence caused by cisplatin. The results suggest that neither an inc rease in the production of NADH-dependent superoxide anion nor a decre ase in activity of several antioxidant enzymes were directly responsib le for cisplatin-induced lipid peroxidation.