Inhibition of S-(1,2-dichlorovinyl)-L-cysteine-induced lipid peroxidation by antioxidants in rabbit renal cortical slices: dissociation of lipid peroxidation and toxicity.
Precision-cut, rabbit renal slices were used to examine the effects of three novel antioxidants (U-74006, U-74500, and U-78517) on S-(1,2-dichlorovinyl)-L-cysteine (DCVC)-induced lipid peroxidation and toxicity. Slices exposed to DCVC showed a dose- and time-dependent increase in lipid peroxidation (TBARS) and a decrease in cellular viability, as evidenced by the loss of intracellular potassium, during the course of a 3 hour incubation. Subsequent studies employed DCVC concentrations of 100 microM. Microemulsion formulations of U-78517, U-74500, and U-74006 (100 microM) inhibited DCVC-induced lipid peroxidation by 100 +/-, 50 +/-, and < 5% (not significant), respectively. However, none of these antioxidants had a significant effect on DCVC-dependent cytotoxicity, as indicated by intracellular potassium release. The effects of U-78517, the most potent of the three antioxidants, were similar to those observed with two model antioxidants, diphenyl-p-phenylenediamine (DPPD) and the iron chelator, deferoxamine. Aminooxyacetic (AOAA), an inhibitor of renal cysteine conjugate beta-lyase, had only a minimal effect on DCVC-induced lipid peroxidation, and no effect on toxicity. These data represent the first report of DCVC-induced lipid peroxidation in rabbit renal cortical slices, a system which has been widely used to investigate mechanisms of nephrotoxicity, including that induced by DCVC. Our results demonstrate that DCVC-induced lipid peroxidation in renal slices can be inhibited by a variety of antioxidant compounds operating by different mechanisms. Because inhibition of lipid peroxidation had minimal effect on DCVC-dependent cytotoxicity, the data suggest that DCVC-induced lipid peroxidation is not a major mechanism in the cytotoxicity induced by this compound.
Davis
J W
JW
Investigative Toxicology, Upjohn Laboratories, Upjohn Co., Kalamazoo, MI 49001.
Petry
T W
TW
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology; D011817:Rabbits; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D002839:Chromans; D010879:Piperazines; D011281:Pregnatrienes; D017392:Thiobarbituric Acid Reactive Substances; C066382:U 78517F; D000625:Aminooxyacetic Acid; C039961:S-(1,2-dichlorovinyl)cysteine; D004247:DNA; C053356:U 74500A; D003676:Deferoxamine; D003545:Cysteine; D011188:Potassium; C053355:tirilazad