Comparative regioselective and sttereosellective metabolism of 7-dhiloroIbe]niz[fl]aini(tIhiiraceiiie amd 7-bromobeinizMaMilIhiiraceinie by momise amid rat liver mcrosomes

Quantitative metabolism of 7-chlorobenz[a]anthracene (7-C1-BA) and 7-bromobenz[a]anthracene (7-Br-BA) by liver microsomes of uninduced mice and rats was studied. Both enzymatic systems metabolize 7-C1-BA preferentially at the C-8 and C-9 aromatic double bond region, -42 and -56% respectively, of the total metabolites. 7-C1-BA and 7-Br-BA were metabolized considerably at C-3 and C-4, C-5 and C-6, C-8 and C-9, and C-10 and C-ll. While 7-C1-BA <rans-3,4-dihydrodiol was formed in a 7-8% yield of the total metabolites in both enzymatic systems, 7-Br-BA trans-3,4-dihdyrodiol was formed 16.0 and 9.9% respectively, from the mouse and rat liver microsomal metabolism. In mutagenicity assays with the Salmonella typhimurium tester strain TA100 in the presence of S9 activation enzymes, both of these fra/w-3,4-dihydrodiols exhibited higher mutagenicity than 7-C1-BA and 7-Br-BA, while the other ftwis-dihydrodiol metabolites were either essentially inactive or weaker than the parent compounds. These results suggest that 7-C1-BA *ra/is-3,4-dihydrodiol and 7-Br-BA *ra/is-3,4-dihydrodiol are the proximate metabolites of 7-CI-BA and 7-Br-BA. Metabolism of 7-CI-BA and 7-Br-BA by mouse liver mkrosomes was also in a stereoselective manner, preferentially giving /nz/u-dihydrodiol metabolites an R, R stereochemistry