Stereoselective metabolism of benzo[a]pyrene and 7-methylbenzo[a]pyrene by liver microsomes from sprague-Dawley rats pretreated with polychlorinated biphenyls.
The dihydrodiols formed from the metabolism of benzo[a]pyrene (BaP) and 7-methylbenzo[a]pyrene (7-MBaP) by liver microsomes from male Sprague-Dawley rats treated with polychlorinated biphenyls (PCBs, Aroclor 1254) have been examined by circular dichroism (CD) spectropolarimetry. Comparisons with optically pure enantiomers obtained via high performance liquid chromatography (HPLC) resolution of diastereomeric di-(-)-menthoxyacetates indicated that the trans-4,5-, 7,8- and 9,10-dihydrodiols formed from BaP metabolism are predominantly R,R-enantiomers with optical purities greater than 98%. The major enantiomers of the metabolically formed 7-MBaP-trans-4,5- and 9,10-dihydrodiols and 7-hydroxymethyl-BaP-trans-9,10-dihydrodiol have Cotton effects very similar to those of BaP-4R,5R- and 9R,10R-dihydrodiols, respectively. These 7-MBaP-trans-4,5- and 9,10-dihydrodiol metabolites therefore contain predominantly the R,R-enantiomers. The optical purity of metabolically formed 7-MBaP-trans-4,5-dihydrodiol was determined to be 30.8% enriched in (-)-enantiomer. The optical purity of the 9,10-dihydrodiol was not determined due to the lack of synthetic standards. The major trans-7,8-dihydrodiol enantiomer formed from 7-MBaP metabolism is a (+)-enantiomer (optical purity 60.4%) which has Cotton effects opposite in sign to that of the (-)-7R,8R-dihydrodiol formed from BaP metabolism. The results indicate that a methyl substituent on a polycyclic aromatic hydrocarbon may alter the stereoselective properties of the microsomal drug-metabolizing enzyme systems toward the substrate molecule.
D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism*; D002942:Circular Dichroism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009905:Optical Rotatory Dispersion; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013379:Substrate Specificity
D001580:Benzopyrenes; D001564:Benzo(a)pyrene; C032121:7-methylbenzo(a)pyrene; D011078:Polychlorinated Biphenyls