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 cleavage of the oxygen-aromatic ring bond. When p-(p-nitrophenoxy)phenol was utilized as a substrate, cleaved products, p-nitrophenol and p-benzoquinone, were formed in two cytochrome P450 model systems, meso-tetraphenylporphinatoiron(III) chloride-NaBH4/O-2 system and meso-tetrakis (2,6-difluorophenyl)porphinatoiron(III) chloride-m-chloroperoxybenzoic acid (mCPBA) system. Rat liver microsomes also catalyzed this reaction, which was inhibited by a cytochrome P450-specific inhibitor, and it was confirmed that this cleavage proceeded in vivo. Further, experiments 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 active 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-nitrophenoxy) 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 that 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 thought to resist metabolism, is cleaved and benzoquinone, a highly toxic metabolite, is formed. (C) 1994 Academic Press, Inc.