Sadzuka Y, Shimizu Y, Takino Y
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Toxicol Lett. 1994 Feb 1;70(2):211-22. doi: 10.1016/0378-4274(94)90165-1.
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.
顺二氯二氨合铂（II）（顺铂）是一种有效的抗肿瘤药物，但会引起剂量依赖性肾毒性。我们研究了顺铂给药后大鼠肾脏中谷胱甘肽S-转移酶（GST）同工酶的变化。顺铂给药后，肾脏GST-α活性降至对照水平的33.4%，GST-μ活性增加了1.9倍。大鼠肾脏GST同工酶的亲和层析证实了这些结果。我们的结果表明，GST同工酶的变化与顺铂诱导的肾毒性有关。我们研究了近端肾小管损伤导致GST同工酶泄漏到尿液中是否能作为顺铂诱导肾毒性的有用标志物。尿液中的总GST和GST-μ活性与血尿素氮（BUN）的变化密切相关，而BUN的变化与顺铂给药后的肾毒性进程密切平行。我们的结果表明，顺铂会降低肾脏GST-μ活性，尽管GST-μ活性作为一种补偿机制增加，但由于这两种同工酶底物特异性的差异，肾毒性仍然出现。
