Time response of carboplatin-induced nephrotoxicity in rats

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. (C) 2004 Elsevier Ltd. All rights reserved.