EVIDENCE FOR CYTOCHROME-P-450 AS A SOURCE OF CATALYTIC IRON IN MYOGLOBINURIC ACUTE-RENAL-FAILURE

Iron has been implicated to play an important role in several models o f tissue injury, including myoglobinuric acute renal failure. In this model, myoglobin released from the injured muscle is generally accepte d as a source of iron. In the present study we measured the bleomycin- detectable iron (iron capable of catalyzing free radical reactions) in the kidneys and examined the role of cytochrome P-450 as a source of catalytic iron in glycerol-induced model of myoglobinuric acute renal failure. Rats were injected with 50% glycerol (8 ml/kg) i.m. after ove rnight water deprivation and sacrificed 24 hours later. There was a ma rked and a specific increase in the bleomycin-detectable iron content accompanied by a marked decrease in the cytochrome P-450 content in th e kidneys of glycerol treated rats. We then examined the effects of tw o different cytochrome P-450 inhibitors, cimetidine (with ranitidine a s a control) and piperonyl butoxide. Cimetidine, but not ranitidine, s ignificantly prevented the increase of bleomycin-detectable iron in th e kidneys of glycerol-treated rats. The loss of cytochrome P-450 conte nt was substantially blocked by both inhibitors, cimetidine and pipero nyl butoxide, but not by ranitidine. Both the inhibitors of cytochrome P-450 provided functional (as measured by BUN and creatinine) and his tological protection against glycerol-induced acute renal failure. Our data thus demonstrate a marked increase in bleomycin-detectable iron in the kidneys of glycerol-treated rats. Our data also indicate that i nhibitors of cytochrome P-450 provide protection against glycerol-indu ced acute renal failure and that cytochrome P-450 may be a significant source of this iron in this model of acute renal failure.