Role of glutathione S-transferase isoenzymes in cisplatin-induced nephrotoxicity in the rat.
cis-Diamminedichloroplatinum(II) (cisplatin) is an effective antitumor agent but causes dose-dependent nephrotoxicity. We examined the changes of glutathione S-transferase (GST) isoenzymes in the rat kidney after cisplatin administration. Renal GST-alpha activity was decreased to 33.4% of the control level and GST-mu activity was increased 1.9-fold after cisplatin administration. These results were confirmed by affinity chromatography of rat renal GST isoenzymes. Our results showed that changes of GST isoenzymes were associated with cisplatin-induced nephrotoxicity. We examined whether GST isoenzymes leaked into the urine by proximal tubular damage could provide a useful marker of cisplatin-induced nephrotoxicity. The total GST and GST-mu activities in urine correlated well with the changes of BUN, which closely parallels the course of nephrotoxicity after cisplatin administration. Our results indicated that renal GST-mu activity was decreased by cisplatin, and although GST-mu activity increased as a compensation mechanism, nephrotoxicity still appeared because of differences in substrate specificity between these two isoenzymes.
Sadzuka
Y
Y
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Shimizu
Y
Y
Takino
Y
Y
D000818:Animals; D002846:Chromatography, Affinity; D002945:Cisplatin / Q000633:toxicity*; D005982:Glutathione Transferase / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D007700:Kinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
D007527:Isoenzymes; D005982:Glutathione Transferase; D002945:Cisplatin