Cell Biology – Immunology – Pathology
Kidney International (1998) 54, 1562–1569; doi:10.1046/j.1523-1755.1998.00161.x
Role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity
Radhakrishna Baliga, Zhiwei Zhang, Mithra Baliga, Norishi Ueda and Sudhir V Shah
Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, Department of Internal Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, and John L. McClellan Memorial VA Hospital, Little Rock, Arkansas, USA
Correspondence: Sudhir V. Shah, M.D., Department of Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Slot 501, Little Rock, Arkansas 72205, USA. E-mail: shahsudhirv@exchange.uams.edu
Received 17 December 1997; Revised 21 May 1998; Accepted 16 June 1998.
Abstract
Role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity.
Background
Iron plays a role in free radical-mediated tissue injury, including cisplatin-induced nephrotoxicity. However, the source of iron (catalyzing free radical reactions) is not known. We examined the role of cytochrome P-450 as a source of catalytic iron in cisplatin-induced nephrotoxicity both in vivo and in vitro.
Methods
Cisplatin-induced acute renal failure was produced in rats by intraperitoneal injection of cisplatin (10 mg/kg body wt). Piperonyl butoxide, a cytochrome P-450 inhibitor, was administered intraperitoneally (400 mg/kg body wt twice at 48-hr intervals) prior to cisplatin injection. The effects of cisplatin in the absence or presence of piperonyl butoxide on the belomycin-detectable iron, cytochrome P-450 content in the kidney, and renal functional and histological changes were evaluated. In an in vitro study, the effect of cytochrome P-450 inhibitors, cimetidine or piperonyl butoxide, on cisplatin-induced cytotoxicity and catalytic iron release from LLC-PK1 cells was examined.
Results
In cisplatin-treated rats, there was a marked decrease in the cytochrome P-450 content specifically in the kidney, accompanied by increased bleomycin-detectable iron content in the kidney. Piperonyl butoxide prevented cisplatin-induced loss of cytochrome P-450 as well as the increase of bleomycin-detectable iron in the kidney, along with both functional and histological protection. Both cimetidine and piperonyl butoxide prevented cisplatin-induced increase in bleomycin-detectable iron and cytotoxicity in LLC-PK1 cells. Treatment of cimetidine did not affect cellular uptake of cisplatin.
Conclusion
Cytochrome P-450, a group of heme proteins, may serve as a significant source of catalytic iron in cisplatin-induced nephrotoxicity.
Keywords:
cimetidine, piperonyl butoxide, LLC-PK1 cells, acute renal failure, free radical, tissue injury, chemotherapeutic agent
