Husai Kazim, Jagannathan Ramesh, Hasan Zeshan, Trammell Gary L, Rybak Leonard P, Hazelrigg Stephen R, Somani Satu M
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-9638, USA.
Pharmacol Toxicol. 2002 Aug;91(2):83-9. doi: 10.1034/j.1600-0773.2002.910207.x.
Abstract: Carboplatin, a second-generation platinum-containing anticancer drug, is currently being used against a variety of cancers. High-dose carboplatin chemotherapy can cause renal tubular injury in cancer patients. However, the biochemical mechanism of carboplatin-induced renal injury has not been well studied. This study investigated the dose response of carboplatin-induced changes in endogenous antioxidants, lipid peroxidation and platinum content in rat kidney. Male Wistar rats (250-300 g) were divided into five groups and treated as follows: (1) control (saline, intraperitoneally); (2) carboplatin (64 mg/kg, intraperitoneally); (3) carboplatin (128 mg/kg, intraperitoneally); (4) carboplatin (192 mg/kg, intraperitoneally); and (5) carboplatin (256 mg/kg, intraperitoneally). The animals were sacrificed four days after treatment. The blood and kidneys were isolated and analyzed. Plasma creatinine and blood urea nitrogen levels were increased significantly in response to carboplatin in a dose-dependent manner. Renal superoxide dismutase and catalase activities were decreased significantly due to carboplatin at dosages of 128 mg/kg and above. The protein expressions of renal copper/zinc-superoxide dismutase and manganese-superoxide dismutase significantly depleted after carboplatin. Carboplatin (192 and 256 mg/kg) significantly increased lipid peroxidation (malondialdehyde concentration) in rat kidneys. Carboplatin dose-dependently increased the renal platinum concentration, with significance at dosages of 128 mg/kg and above. Carboplatin (256 mg/kg) significantly increased renal xanthine oxidase activity, while ratio of reduced to oxidized glutathione depleted significantly. The data suggested that carboplatin caused dose-dependent oxidative renal injury, as evidenced by renal antioxidant depletion, enhanced lipid peroxidation, platinum content, plasma creatinine and blood urea nitrogen levels in rats.
卡铂是一种第二代含铂抗癌药物，目前正用于治疗多种癌症。高剂量卡铂化疗可导致癌症患者肾小管损伤。然而，卡铂诱导肾损伤的生化机制尚未得到充分研究。本研究调查了卡铂诱导的大鼠肾脏内源性抗氧化剂、脂质过氧化和铂含量变化的剂量反应。将雄性Wistar大鼠（250 - 300克）分为五组并进行如下处理：（1）对照组（腹腔注射生理盐水）；（2）卡铂组（64毫克/千克，腹腔注射）；（3）卡铂组（128毫克/千克，腹腔注射）；（4）卡铂组（192毫克/千克，腹腔注射）；（5）卡铂组（256毫克/千克，腹腔注射）。处理四天后处死动物。分离血液和肾脏并进行分析。血浆肌酐和血尿素氮水平随着卡铂剂量的增加而显著升高，呈剂量依赖性。卡铂剂量在128毫克/千克及以上时，肾脏超氧化物歧化酶和过氧化氢酶活性显著降低。卡铂处理后，肾脏铜/锌超氧化物歧化酶和锰超氧化物歧化酶的蛋白表达明显减少。卡铂（192和256毫克/千克）显著增加大鼠肾脏的脂质过氧化（丙二醛浓度）。卡铂剂量依赖性地增加肾脏铂浓度，在128毫克/千克及以上剂量时具有显著性。卡铂（256毫克/千克）显著增加肾脏黄嘌呤氧化酶活性，而还原型谷胱甘肽与氧化型谷胱甘肽的比例显著降低。数据表明，卡铂可导致剂量依赖性的氧化性肾损伤，表现为大鼠肾脏抗氧化剂耗竭、脂质过氧化增强、铂含量增加、血浆肌酐和血尿素氮水平升高。
