Comparative regioselective and stereoselective metabolism of 7-chlorobenz[a]anthracene and 7-bromobenz[aanthracene and 7-bromobenz[a]anthracene by mouse and rat liver microsomes

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Abstract
Quantitative metabolism of 7-chlorobenz[aanthracene (7-ClBA) and 7-bromobenz[a]anthracene (7-Br-BA) by liver microsomes of uninduced mice and rats was studied. Both enzymatic systems metabolize 7-Cl-BA preferentially at the C-8 and C-9 aromatic double bond region, ∽42 and ∽56% respectively, of the total metabolites. 7-Cl-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-11. While 7-Cl-BA trans-3,4-dihydrodiol was formed in a 7–8% yield of the total metabolites in both enzymatic systems, 7-Br-BA trans-3,4-dihdyrodlol was formed 16.0 and 9.9% respectively, from the mouse and rat liver microsomal metabolism. In mutagenicity assays vith the Salmonella typhimurium tester strain TA100 in the presence of S9 activation enzymes, both of these trans-3,4-dihydrodiols exhibited higher mutagenicity than 7-Cl-BA and 7-Br-BA, while the other trans-dihydrodiol metabolites were either essentially inactive or weaker than the parent compounds. These results suggest that 7-Cl-BA trans-3,4-dihydrodiol and 7-Br-BA trans-3,4-dihydrodiol are the proximate metabolites of 7-Cl-BA and 7-Br-BA. Metabolism of 7-Cl-BA and 7-Br-BA by mouse liver microsomes was also in a stereoselective manner, preferentially giving trans-dihydrodiol metabolites an R, R stereochemistry.

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