Potentiation of cisplatin-induced lipid peroxidation in kidney cortical slices by glutathione depletion.
Effects of cis-diamminedichloroplatinum II (cisplatin), an antitumor agent with a dose-limiting effect of nephrotoxicity, on lipid peroxides and glutathione (GSH) were examined in rat kidney cortical slices treated with or without diethylmaleate (DEM), a GSH depletor, in vitro. DEM (3 mM) decreased the GSH level to about 16% of the control with a concomitant increase in lipid peroxides after 90 min of incubation. The same effects were obtained with 1 mM cisplatin 90 min later. Cisplatin (1 mM) with DEM (2 mM) stimulated both the decrease in GSH and the increase in lipid peroxides 90 min after incubation. However, cisplatin with DEM markedly stimulated lipid peroxidation with a small effect on the GSH decrease by cisplatin alone 30 min after incubation, while each drug by itself did not affect lipid peroxidation. The antioxidants N,N'-diphenyl-p-phenylene-diamine (DPPD), promethazine, and ascorbic acid abolished cisplatin-induced lipid peroxidation in the presence of DEM. DPPD had no effect on the depletion of GSH caused by cisplatin and DEM. Ascorbic acid and promethazine caused only a slight return towards the control level. The results suggested that cisplatin-induced lipid peroxidation is due to another mechanism in addition to the GSH depletion caused by the antitumor drug.
Division of Pharmacology, Osaka University of Pharmaceutical Sciences, Japan.
S
S
Nakano
M
M
Gemba
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002945:Cisplatin / Q000633:toxicity*; D004357:Drug Synergism; D005978:Glutathione / Q000172:deficiency*; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D008298:Maleates; C014476:diethyl maleate; D005978:Glutathione; D002945:Cisplatin