NOVEL METABOLIC PATHWAY OF ARYLETHERS BY CYTOCHROME-P450 - CLEAVAGE OF THE OXYGEN-AROMATIC RING BOND ACCOMPANYING IPSO-SUBSTITUTION BY THE OXYGEN-ATOM OF THE ACTIVE SPECIES IN CYTOCHROME-P450 MODELS AND CYTOCHROME-P450

We have found a novel metabolic pathway of arylethers, involving the c leavage of the oxygen-aromatic ring bond. When p-(p-nitrophenoxy)pheno l was utilized as a substrate, cleaved products, p-nitrophenol and p-b enzoquinone, were formed in two cytochrome P450 model systems, meso-te traphenylporphinatoiron(III) chloride-NaBH4/O-2 system and meso-tetrak is (2,6-difluorophenyl)porphinatoiron(III) chloride-m-chloroperoxybenz oic acid (mCPBA) system. Rat liver microsomes also catalyzed this reac tion, which was inhibited by a cytochrome P450-specific inhibitor, and it was confirmed that this cleavage proceeded in vivo. Further, exper iments using [O-18]mCPBA and O-18(2) proved that the cleavage reaction is accompanied with the ipso-substitution by the oxygen atom of the a ctive species in both cytochrome P450 model system and cytochrome P450 . When the microsomal reactions of p-(p-nitrophenoxy)phenol analogues which lack a hydroxy group, namely p-nitrophenoxybenzene, p-(p-nitroph enoxy) anisole, and p-(p-nitrophenoxy) toluene, were investigated, the cleavage reaction occurred via p-(p-nitrophenoxy)phenol in the cases of p-nitrophenoxybenzene and p-(p-nitrophenoxy)anisole, indicating tha t a hydroxy group at the p-position to the ether bond is necessary for this pathway. This metabolic pathway appears to be important, because a diarylether linkage, which is very stable and has generally been th ought to resist metabolism, is cleaved and benzoquinone, a highly toxi c metabolite, is formed. (C) 1994 Academic Press, Inc.