Metabolic pathways of 7,12-dimethylbenz[a]anthracene in hepatic microsomes

Abstract

High pressure liquid chromatography has enabled quantitative analysis of the in vitro metabolism of 7,12-dimethylbenz[a]anthracene, 7-methyl-12-hydroxymethylbenz[a]anthracene, 7-hydroxymethyl-12-methylbenz[a]anthracene, and 7,12-dihydroxymethylbenz[a]anthracene by 3-methylcholanthrene-induced and control rat liver microsomes. The following previously unrecognized metabolites have been tentatively identified: 5,6-dihydro-5,6-dihydroxy-7-methyl-12-hydroxymethylbenz[a]anthracene, 3-hydroxy-7,12-dihydrodihydroxymethylbenz[a]anthracene, 4-hydroxy-7,12-dihydrodihydroxymethylbenz[a]anthracene, and 8,9-dihydro-8,9-dihydroxy-7,12-dihydroxymethylbenz[a]anthracene. The epoxide hydratase inhibitor 1,2-epoxy-3,3,3-trichloropropane was found to eliminate all dihydrodiol formation and markedly inhibit the formation of several dimethylbenzanthracene metabolites. It is proposed that the tentatively identified 3-hydroxy and 4-hydroxy derivatives are formed by an enzymatic mechanism that does not involve epoxides as intermediates. The metabolic pathways of 7,12-dimethylbenz[a]anthracene in hepatic microsomal enzymes are proposed.