Microbial models of mammalian metabolism: conversion of warfarin to 4'-hydroxywarfarin using Cunninghamella bainieri.
Warfarin, an anticoagulant and "metabolic probe" for cytochrome P-450 isozyme multiplicity, is metabolized to 4'-hydroxywarfarin, a principle mammalian metabolite, using the fungus Cunninghamella bainieri (UI-3065). The metabolite was isolated from cell suspension cultures and characterized by analytical (TLC, HPLC, GC-MS) and spectral (HRMS, EI-MS, PMR) comparisons with authentic 4'-hydroxywarfarin. The mechanism of aromatic hydroxylation was examined in C. bainieri using 4'-deuterowarfarin. The absence of a primary isotope effect (KH/KD = 1.13), migration and retention of deuterium in the phenolic product [80% migration and retention (M&R)], and inhibition of the hydroxylation by carbon monoxide (93% inhibition in a 50:50 CO:O2 atmosphere) are consistent with a cytochrome P-450-mediated hydroxylation involving the classic NIH shift (arene oxide) pathway.
Rizzo
J D
JD
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Texas, Austin 78712-1074.
Davis
P J
PJ
D002248:Carbon Monoxide / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006900:Hydroxylation; D007202:Indicators and Reagents; D008954:Models, Biological; D009090:Mucorales / Q000201:enzymology / Q000378:metabolism*; D012997:Solvents; D014859:Warfarin / Q000031:analogs & derivatives* / Q000378:metabolism*
D007202:Indicators and Reagents; D012997:Solvents; C059853:4'-hydroxywarfarin; D014859:Warfarin; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System