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Metabolic activation of furosemide to a chemically reactive, hepatotoxic metabolite.

The possibility that furosemide-induced hepatic necrosis results from the formation of a chemically reactive hepatotoxic metabolite has been examined. Hepatotoxic doses of 3H-furosemide or 14C-furosemide were administered to normal mice and to mice pretreated with piperonyl butoxide, cobalt chloride, alpha-naphthylisothiocyanate or phenobarbital. Mice were killed at various time intervals and tissues were examined for necrosis, for free furosemide concentrations and for covalently bound metabolites of furosemide. Little furosemide was covalently bound to muscle, whereas the amount of covalently bound material in liver usually paralleled the severity of live necrosis after alteration by the pretreatments. The severity of hepatic necrosis failed to correlate with furosemide concentrations in liver or plasma. Furosemide was shown to be metabolically activated to an arylating intermediate by a cytochrome P-450 mixed function oxidase in hepatic microsomes. Additional experiments demonstrated that the furan ring of furosemide was the portion activated.