The destruction of cytochrome P-450 by alclofenac: possible involvement of an epoxide metabolite.

The metabolism of alclofenac (4-allyloxy-3-chlorophenyl acetic acid) and its ability to induce destruction of cytochrome P-450 was studied in mouse hepatic microsomes obtained from control animals or animals pretreated with phenobarbitone (PB) or 3-methyl-cholanthrene (3-MC). No evidence was obtained for metabolism of alclofenac in control microsomes although in induced microsomes alclofenac was metabolised to both the dihydroxy (DHA) and phenolic (4-hydroxy-3-chlorophenyl acetic acid: HCPA) metabolites. Significant destruction of cytochrome P-450 was observed when alclofenac was incubated with microsomes from mice pretreated with PB but not from untreated or 3-MC-treated mice. This destruction is dependent on the presence of a NADPH-regenerating system and in inhibited in the presence of SKF-525A, metyrapone, glutathione and cysteine. The stable metabolites DHA and HCPA caused no loss of cytochrome P-450 whereas the reactive intermediate, alclofenac epoxide, was a potent inducer of destruction in the absence of NADPH. These results suggest that destruction of cytochrome P-450 by alclofenac in vitro is mediated, at least in part, through the formation of a reactive epoxide metabolite.