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.


CONCLUSIONS
Cytochrome P-450, a group of heme proteins, may serve as a significant source of catalytic iron in cisplatin-induced nephrotoxicity.
Baliga
R
R
Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Zhang
Z
Z
Baliga
M
M
Ueda
N
N
Shah
S V
SV
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology; D002945:Cisplatin / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D017665:Hydroxyl Radical; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D010882:Piperonyl Butoxide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D001761:Bleomycin; D017665:Hydroxyl Radical; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D010882:Piperonyl Butoxide; D002945:Cisplatin