Stereoselectivity of rat liver cytochrome P-450 isozymes: direct determination of enantiomeric composition of K-region epoxides formed in the metabolism of benz[a]anthracene and 7,12-dimethylbenz[a]anthracene.
The K-region 5,6-epoxides of benz[a]anthracene (BA) and 7,12-dimethylbenz[a]anthracene (DMBA) were isolated by normal-phase HPLC from metabolites formed by incubation of the respective parent compound with liver microsomes from untreated (control), phenobarbital (PB)-treated, and 3-methylcholanthrene (MC)-treated rats in the presence of an epoxide hydrolase inhibitor, 3,3,3-trichloropropylene 1,2-oxide. The enantiomeric contents of the metabolically formed K-region 5,6-epoxides of BA and DMBA were directly determined by chiral stationary phase HPLC. The K-region 5,6-epoxides formed in the metabolism of BA have (5R,6S): (5S,6R) enantiomer ratios of 25:75 (control), 21:79 (PB), and 4:96 (MC), respectively. In contrast, the (5R,6S):(5S,6R) enantiomeric ratios of the K-region 5,6-epoxides formed in the metabolism of DMBA are 76:24 (control), 80:20 (PB), and 97:3 (MC), respectively. These and earlier results on the stereoselective K-region metabolism studies of 7-methylbenz[a]anthracene and 12-methylbenz[a]anthracene indicate that cytochrome P-450 isozymes exhibit different stereoselectivities in the K-region epoxidations of BA and DMBA and a methyl substituent at the C12 position of BA alters the stereoheterotopic interactions between cytochrome P-450 isozymes and the BA molecule.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism; D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004852:Epoxy Compounds / Q000302:isolation & purification / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013379:Substrate Specificity
D001551:Benz(a)Anthracenes; D004852:Epoxy Compounds; D007527:Isoenzymes; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; C030935:benz(a)anthracene