Metabolism of 6-methylbenz[a]anthracene by rat liver microsomes and mutagenicity of metabolites.

6-Methylbenz[a]anthracene (6-MBA) is metabolized by rat liver microsomes to form 3-hydroxy-6-MBA, 4-hydroxy-6-MBA, 5-hydroxy-6-MBA, 6-MBA trans-3,4-, 5,6-, 8,9-, and 10,11-dihydrodiols, and 4-hydroxy-6-MBA trans-10,11-dihydrodiol as the identifiable metabolites. 6-Hydroxymethylbenz[a]anthracene and its phenolic and dihydrodiol metabolites are also formed. The unique metabolites identified in 6-MBA metabolism are 6-MBA trans-5,6-dihydrodiol and 4-hydroxy-6-MBA trans-10,11-dihydrodiol. Metabolites were isolated by reversed-phase and normal-phase high-performance liquid chromatographies and identified by UV-visible absorption, mass, and proton nuclear magnetic resonance spectral analyses. Metabolites formed by low and high concentrations of liver microsomal enzymes from untreated, phenobarbital-treated, and 3-methylcholanthrene-treated male Sprague-Dawley rats were quantified by using [3H]6-MBA, with the tritium labeled at the methyl carbon, and liquid scintillation counting of fractions collected from reversed-phase high-performance liquid chromatography. Metabolic formations of 6-hydroxymethylbenz[a]anthracene, 6-MBA trans-dihydrodiols, and 4-hydroxy-6-MBA trans-10,11-dihydrodiol are highly dependent on the contents of cytochrome P-450 isozymes present in liver microsomes. The relative mutagenic activities of metabolites toward Salmonella typhimurium TA100 are: 6-MBA trans-3,4-dihydrodiol greater than 6-MBA trans-8,9-dihydrodiol greater than 6-MBA greater than 6-MBA trans-10,11-dihydrodiol greater than 4-hydroxy-6-MBA congruent to 4-hydroxy-6-MBA trans-10,11-dihydrodiol. The relatively high mutagenic activities of 6-MBA trans-3,4-dihydrodiol and 6-MBA trans-8,9-dihydrodiol suggest that both 6-MBA trans-3,4-dihydrodiol 1,2-epoxide(s) and 6-MBA trans-8,9-dihydrodiol 10,11-epoxide(s) may be the major metabolites which contribute to the carcinogenic properties of 6-MBA.