Nakamura M, Imaoka S, Tanaka E, Misawa S, Funae Y
Laboratory of Chemistry, Osaka City University Medical School, Japan.
Res Commun Mol Pathol Pharmacol. 1998 Jan;99(1):23-32.
Effects of cis-diamminedichloroplatinum (cisplatin) on rat kidney were investigated. Clinical parameters in rat urine and blood were studied. Blood urea nitrogen (BUN) and creatinine in blood and K+ in urine increased, but Na+ in urine decreased. Contents of total P450 and metabolic activities towards lauric acid and arachidonic acid in rat renal microsomes were not changed by cisplatin treatment. The levels of P450 isozymes (CYP4A1, 4A2, 4A8 and 2C23) were determined in rat renal microsomes by immunoblotting. The levels of CYP4A2 and 4A8 which are lauric acid omega-hydroxylases were not changed, but the levels of CYP2C23 and 4A1 were increased significantly by cisplatin treatment. Effects of clofibrate, a typical inducer for CYP4A1, on rat kidney were compared with those of cisplatin. Clofibrate induced palmitoyl CoA oxidase (a marker enzyme of peroxysome), CYP4A1, and CYP4A2 and reduced triglyceride level in plasma. Cisplatin had similar effects to clofibrate and induced peroxysomes as well as CYP4A1, although the effects were at a lesser extent than those of clofibrate. The induction levels of CYP4A1 correlated with increased levels of BUN. The present findings suggest that induction of P450 by cisplatin may take part in the renal injury or nephrotoxicity of cisplatin.
研究了顺二氯二氨铂（顺铂）对大鼠肾脏的影响。对大鼠尿液和血液中的临床参数进行了研究。血液中的血尿素氮（BUN）和肌酐以及尿液中的钾离子增加，但尿液中的钠离子减少。顺铂处理并未改变大鼠肾微粒体中总P450的含量以及对月桂酸和花生四烯酸的代谢活性。通过免疫印迹法测定大鼠肾微粒体中P450同工酶（CYP4A1、4A2、4A8和2C23）的水平。作为月桂酸ω-羟化酶的CYP4A2和4A8的水平未发生变化，但顺铂处理后CYP2C23和4A1的水平显著增加。将CYP4A1的典型诱导剂氯贝丁酯对大鼠肾脏的影响与顺铂的影响进行了比较。氯贝丁酯诱导棕榈酰辅酶A氧化酶（过氧化物酶体的标志物酶）、CYP4A1和CYP4A2，并降低血浆中的甘油三酯水平。顺铂具有与氯贝丁酯相似的作用，并诱导过氧化物酶体以及CYP4A1，尽管其作用程度小于氯贝丁酯。CYP4A1的诱导水平与BUN水平的升高相关。目前的研究结果表明，顺铂诱导P450可能参与顺铂的肾损伤或肾毒性。
