Comparisons of warfarin metabolism by liver microsomes of rats treated with a series of polybrominated biphenyl congeners and by the component-purified cytochrome P-450 isozymes.
R- and S-warfarin metabolite profiles (regio- and stereoselectivity) has been determined with hepatic microsomes from untreated rats and rats treated with nine individual polybrominated biphenyl (PBB) congeners, a commercial mixture of PBBs, and, for comparison with phenobarbital and 3-methylcholanthrene. The metabolic rates have been correlated with cytochrome P-450 (P-450) isozyme concentrations in the microsomes determined by immunochemical quantitation techniques (G.A. Dannan, F.P. Guengerich, L.S. Kaminsky, and S.D. Aust, (1983) J. Biol. Chem. 258, 1282-1288). The warfarin hydroxylase activities of the P-450 isozyme components of the various microsomal preparations (F.P. Guengerich, G.A. Dannan, S.T. Wright, M.V. Martin, and L.S. Kaminsky (1982) Biochemistry 21, 6019-6030) were multiplied by the corresponding isozyme concentrations to obtain an assessment of the potential warfarin hydroxylase capacity of the microsomes, and the results were compared with actual activities. The results of these studies and comparisons indicate that substrate regio- and stereoselectivities of microsomal-bound P-450s are essentially retained on purification of the isozymes to homogeneity and reconstitution, that warfarin metabolism by microsomal preparations can be used to predict microsomal P-450 isozyme compositions, and that microsomal warfarin hydroxylase activity is greater than would be predicted based on the approx 20:1 ratio of P-450 to NADPH-P-450 reductase in the microsomes and on the known activities of constituent isozymes. Two P-450 isozymes which are induced by treatment of rats with phenobarbital appear to be more tightly linked to NADPH-P-450 reductase than does an isozyme induced by beta-naphthoflavone.
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification* / Q000378:metabolism; D007527:Isoenzymes / Q000302:isolation & purification* / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D011075:Polybrominated Biphenyls / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D014859:Warfarin / Q000378:metabolism*
D001713:Biphenyl Compounds; D007527:Isoenzymes; D011075:Polybrominated Biphenyls; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System