Differential effects of cisplatin on the production of NADH-dependent superoxide and the activity of antioxidant enzymes in rat renal cortical slices in vitro.
Cisplatin-induced cytotoxicity has been investigated with rat renal cortical slices in vitro. Incubation of renal slices with cisplatin caused an unexpected decrease in NADH-dependent. lucigenin-enhanced chemiluminescence in the homogenate of the slices in a time- and concentration-dependent fashion. Cisplatin caused a concentration-related (0.2 1 mM) decrease in the formation of NADH-dependent superoxide anion. Cisplatin (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 slices with 0.25 mM cisplatin. In addition, the activities of superoxide dismutase (SOD) and catalase in the slices were significantly increased after 60 min. of exposure to cisplatin (2 mM) while decreases in the activities of glutathione (GSH) peroxidase and GSSG reductase became significant at 90 and 120 min. of incubation respectively. SOD and catalase activities were increased by 1.6 and 1.5 fold respectively after 90 min. of incubation and the activities of GSH peroxidase and GSSG reductase were decreased to 82% and 72% of control, respectively at 120 min. Both dithiothreitol (2 mM), a sulphydryl agent and diphenylphenylenediamine (5 microM), an antioxidant, protected against cisplatin-induced leakage of lactate dehydrogenase, lipid peroxidation and decreases of GSH peroxidase and GSSG reductase but had no effect on the decrease of chemiluminescence caused by cisplatin. The results suggest that neither an increase in the production of NADH-dependent superoxide anion nor a decrease in activity of several antioxidant enzymes were directly responsible for cisplatin-induced lipid peroxidation.
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
J G
JG
Zhang
W E
WE
Lindup
D000166:Acridines / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects*; D008163:Luminescent Measurements; D009249:NADP / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides
D000166:Acridines; D000970:Antineoplastic Agents; D000975:Antioxidants; D010655:Phenylenediamines; D013439:Sulfhydryl Reagents; D013481:Superoxides; C033472:10,10'-dimethyl-9,9'-biacridinium; D009249:NADP; C004845:N,N'-diphenyl-4-phenylenediamine; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D002945:Cisplatin; D004229:Dithiothreitol