Dose response of carboplatin-induced nephrotoxicity in rats.
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.
Husai
Kazim
K
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-9638, USA. khusain@siumed.edu
Jagannathan
Ramesh
R
Hasan
Zeshan
Z
Trammell
Gary L
GL
Rybak
Leonard P
LP
Hazelrigg
Stephen R
SR
Somani
Satu M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000633:toxicity*; D016190:Carboplatin / Q000009:adverse effects / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D003404:Creatinine; D016190:Carboplatin; D013482:Superoxide Dismutase