阿西维辛或谷胱甘肽降低顺铂引起的肾脏毒性和顺铂-DNA加合物在鼠肾脏中的水平

摘要

目的为了了解阿西维辛(acivicin)和GSH预防肾脏毒性的机制,研究了顺铂-DNA加合物在大鼠肾脏中的水平.方法顺铂(6 mg·kg-1)从尾静脉注入大鼠,5 d后处死.其他两组动物在给顺铂前2.5 h,给予阿西维辛或者GSH.测量顺铂-DNA加合物在肾脏中的浓度、血中尿素氮(BUN)和丝氨酸肌酸的浓度.结果在给顺铂前2.5 h,给10 mg·kg-1阿西维辛完全阻断了顺铂引起的肾脏毒性.具体表现是血氮和肌酸浓度降低,DNA加合物减少了17.1%(P<0.05).在给顺铂前,给500 mg·kg-1 GSH,肾脏毒性和顺铂-DNA加合物水平均显著性减低(P<0.05).另外,在DNA加合物和血氮之间存在着一个弱正相关关系.结论 DNA加合物在顺铂引起的肾脏毒性中引了一些作用.但是DNA加合物和血氮之间的弱相关关系提示DNA加合物与肾脏毒性只有较弱的联系,在顺铂引起的肾脏毒性中不是主要因素.%AIM In order to examine the mechanisms by which these compounds prevent the development of nephrotoxicity, we investigated cisplatin-DNA adduct formation in kidneys of rats given either cisplatin alone or pretreatments with acivicin or GSH. METHODS Rats were given cisplatin 6 mg·kg-1 body weight by tail vein injection and sacrificed 5 days later. RESULTSPretreatment with acivicin 10 mg·kg-1 body weight 2.5 h before the cisplatin completely blocked cisplatin-induced nephrotoxicity, as determined by blood urea nitrogen(BUN) and serine creatinine, and reduced renal DNA adducts by 17.1% (not statistically significant). Pretreatment with GSH 500 mg·kg-1 body weight significantly reduced nephrotoxicity and lowered cisplatin-DNA adduct levels by 45.2% (P<0.05). In addition, a weakly-positive linear relationship was observed between cisplatin-DNA adducts and BUN level (r=0.47, P=0.03), and adducts and serum creatinine level (r=0.50, P=0.02). CONCLUSION The associations observed between cisplatin-DNA adduct levels and these nephrotoxic end points suggest that cisplatin-DNA adducts or their correlates be only weakly associated with kidney damage. The lack of strong associations here supports the conclusion that cisplatin-DNA adducts are not the major cause of cisplatin-induced kidney toxicity.