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

• Published in: Archives of biochemistry and biophysics Vol. 310; no. 2; p. 402
• Main Authors: Ohe, T, Mashino, T, Hirobe, M
• Format: Journal Article
• Language: English
• Published: United States 01-05-1994
• Subjects: Animals; Cytochrome P-450 Enzyme System - metabolism; Indicators and Reagents; Kinetics; Male; Microsomes, Liver - enzymology; Molecular Structure; Nitrophenols - metabolism; Oxygen Isotopes; Phenyl Ethers - metabolism; Rats; Rats, Wistar; Substrate Specificity
• ISSN: 0003-9861
• DOI: 10.1006/abbi.1994.1185

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/O2 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 [18O]mCPBA and 18O2 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.