STEREOSELECTIVITY OF RAT-LIVER MICROSOMAL-ENZYMES IN THE METABOLISM OF 7-FLUOROBENZ(A)ANTHRACENE AND MUTAGENICITY OF METABOLITES

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (2) , 562-570
Abstract
7-Fluorobenz(a)anthracene (7-FBA) was metabolized by rat liver microsomes predominantly to 4-hydroxy-7-FBA and 7-FBA trans-3,4-, 5,6-, 8,9-, and 10,11-dihydrodiols. The fluoro substituent causes 7-FBA trans-5,6- and 8,9-dihydrodiols to adopt preferentially quasidiaxial conformations. The major enantiomers of the quasidiaxial trans-5,6- and trans-8,9-dihydrodiols were determined by the exciton chirality method to have R,R absolute stereochemistries. By comparing with the circular dichroism spectra of BA 3R,4R- and 10R,11R-dihydrodiols, the major enantiomers of the quasidiequatorial 7-FBA trans-3,4- and trans-10,11-dihydrodiols were also found to have R,R, absolute configurations. All four 7-FBA trans-dihydrodiol metabolites obtained from incubations of 7-FBA with liver microsomes prepared from untreated and 3-methylcholanthrene-, phenobarbital-, and polychlorinated biphenyl-treated male Sprague-Dawley rats were enriched in R,R enantiomers, differing only in optical purities. Pretreatment of rats with phenobarbital, 3-methylcholanthrene and polychlorinated biphenyls changed the rate of 7-FBA metabolism by 0.47-, 1.14- and 1.70-fold, respectively. Pretreatment of rats with enzyme inducers also altered the quantitative distribution of metabolites formed. The relative mutagenic activities of metabolites toward Salmonella typhimurium TA 100 were: 7-FBA trans-3,4-dihydrodiol > 7-FBA trans-10,11-dihydrodiol > 7-methyl-BA .apprxeq. 7-FBA > 7-FBA trans-8,9-dihydrodiol .apprxeq. 7-methyl-BA trans-10,11-dihydrodiol > 7-FBA trans-5,6-dihydrodiol .apprxeq. 4-hydroxy-7-FBA. The relatively high mutagenic activities of 7-FBA trans-3,4- and trans-10,11-dihydrodiols suggest that both 7-FBA trans-3,4-dihydrodiol 1,2-epoxide(s) and 7-FBA trans-10,11-dihydrodiol 8,9-epoxide(s) may be the major metabolites which contribute to the carcinogenic properties of 7-FBA.