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/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.
Ohe
T
T
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Mashino
T
T
Hirobe
M
M
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007202:Indicators and Reagents; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D009596:Nitrophenols / Q000378:metabolism*; D010103:Oxygen Isotopes; D010647:Phenyl Ethers / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
D007202:Indicators and Reagents; D009596:Nitrophenols; D010103:Oxygen Isotopes; D010647:Phenyl Ethers; C087077:4-(4-nitrophenoxy)phenol; D003577:Cytochrome P-450 Enzyme System