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.
D000818:Animals; D003545:Cysteine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000201:enzymology; D010648:Phenylacetates / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D011335:Proadifen / Q000494:pharmacology
D010648:Phenylacetates; C025212:alclofenac epoxide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D005978:Glutathione; D003545:Cysteine; D008797:Metyrapone