Stereoselective formations of enantiomeric K-region epoxide and trans-dihydrodiols in dibenz[a,h]anthracene metabolism.
Metabolism of dibenz[a,h]anthracene (DBA) to optically active epoxide and dihydrodiol products by rat liver microsomes was investigated. Enantiomeric separation of K-region 5,6-epoxide, trans- and cis-5,6-dihydrodiols, non-K-region trans-1,2- and trans-3, 4-dihydrodiols, and O-methyl ethers derived from methoxylation of racemic and enantiomeric K-region 5,6-epoxides was performed on HPLC columns packed with Pirkle chiral stationary-phase (CSP) (R)-N-(3,5-dinitrobenzoyl)phenylglycine (R-DNBPG) or (S)-N-(3,5-dinitrobenzoyl) leucine (S-DNBL), which was either ionically or covalently bonded to a silica gel support. Enantiomers of DBA 5,6-epoxide, trans-5,6-dihydrodiol, and its two isomeric O-methyl ethers were efficiently separated on the ionically bonded R-DNBPG column. Enantiomers of DBA cis-5, 6-dihydrodiol were resolved on both ionically and covalently bonded S-DNBL columns. Enantiomeric pairs of the non-K-region trans-1,2- and 3,4-dihydrodiols were poorly resolved on all CSPs tested. DBA was incubated with a NADPH-regenerating system and liver microsomes from untreated, phenobarbital- (PB) treated, 3-methylcholanthrene- (MC) treated, and polychlorinated biphenyl (PCB, Aroclor 1254) treated rats either in the absence or in the presence of an epoxide hydrolase inhibitor, 3,3,3-trichloropropylene 1,2-oxide (TCPO). Metabolites formed were analyzed by reversed-phase, normal-phase, and CSP HPLC. CD spectral and CSP-HPLC analyses of metabolically formed trans-dihydrodiols indicated that the dihydrodiols are highly enriched in the R,R-enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)
Mushtaq
M
M
Department of Pharmacology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799.
Weems
H B
HB
Yang
S K
SK
D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism*; D006859:Hydrogen / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D010636:Phenols / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D001551:Benz(a)Anthracenes; D004852:Epoxy Compounds; D010636:Phenols; D006859:Hydrogen; D004851:Epoxide Hydrolases; C026486:1,2,5,6-dibenzanthracene