Husain Kazim, Whitworth Craig, Rybak Leonard P
Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA.
Pharmacol Res. 2004 Sep;50(3):291-300. doi: 10.1016/j.phrs.2004.04.001.
Carboplatin, a second-generation platinum-containing anti-cancer drug, is currently being used against human cancers. High-dose carboplatin chemotherapy can cause renal tubular injury in cancer patients. We have shown a dose-dependent nephrotoxicity of carboplatin in a rat model. However, the time response of carboplatin-induced renal injury has not been explored. This study investigated the time response of carboplatin-induced nephrotoxicity in rat. Male Wistar rats (250-300 g) were divided into two groups of 30 animals each and treated as follows: (1) control (saline, intraperitoneally) and (2) carboplatin (256 mg kg(-1), intraperitoneally). The animals (n = 6) from each group were sacrificed 1-5 days after treatment. The blood and kidneys were isolated and analyzed. Plasma creatinine, blood urea nitrogen (BUN), and blood urea levels were increased significantly in response to carboplatin in a time-dependent manner, indicating potential nephrotoxicity. Carboplatin time-dependently increased the renal platinum concentration, renal xanthine oxidase activity, increased membrane lipid peroxidation (MDA) concentration, while ratio of reduced-to-oxidized glutathione (GSH/GSSG) depleted significantly, indicating oxidative renal injury. Renal anti-oxidant enzymes, such as cytosolic copper/zinc-superoxide dismutase (CuZn-SOD) and mitochondrial manganese (Mn)-SOD, catalase (CAT), and glutathione peroxidase (GSH-Px) activities were decreased significantly due to carboplatin 3-5 days post-treatment. The protein expressions of renal CuZn-SOD and Mn-SOD significantly depleted 3-5 days after carboplatin administration, indicating decline in de novo synthesis of enzyme proteins. The data suggested that carboplatin caused time-dependent oxidative renal injury, as evidenced by renal anti-oxidant depletion, enhanced lipid peroxidation, platinum content, plasma creatinine BUN, and blood urea levels in rats.
卡铂是一种第二代含铂抗癌药物，目前正在用于治疗人类癌症。高剂量卡铂化疗可导致癌症患者肾小管损伤。我们已经在大鼠模型中证明了卡铂具有剂量依赖性肾毒性。然而，卡铂诱导的肾损伤的时间反应尚未得到研究。本研究调查了卡铂诱导大鼠肾毒性的时间反应。将雄性Wistar大鼠（250 - 300克）分为两组，每组30只动物，并进行如下处理：（1）对照组（腹腔注射生理盐水）和（2）卡铂组（腹腔注射256毫克/千克）。每组6只动物在治疗后1 - 5天处死。分离血液和肾脏并进行分析。血浆肌酐、血尿素氮（BUN）和血尿素水平随着卡铂作用时间的延长而显著升高，表明存在潜在的肾毒性。卡铂使肾铂浓度、肾黄嘌呤氧化酶活性随时间依赖性增加，膜脂质过氧化（MDA）浓度升高，而还原型谷胱甘肽与氧化型谷胱甘肽的比值（GSH/GSSG）显著降低，表明存在氧化性肾损伤。肾抗氧化酶，如胞质铜/锌超氧化物歧化酶（CuZn - SOD）、线粒体锰（Mn）- SOD、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GSH - Px）的活性在治疗后3 - 5天因卡铂作用而显著降低。卡铂给药后3 - 5天，肾CuZn - SOD和Mn - SOD的蛋白表达显著减少，表明酶蛋白的从头合成下降。数据表明，卡铂导致时间依赖性氧化性肾损伤，大鼠肾抗氧化剂耗竭、脂质过氧化增强、铂含量增加、血浆肌酐、BUN和血尿素水平升高证明了这一点。
