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Metabolism of 6-Methylbenz[a]anthracene by Rat Liver Microsomes and Mutagenicity of Metabolites¹

Department of Pharmacology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799 [M. M., S. K. Y.], and National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079 [P. P. F., D. W. M.]

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 > 6-MBA trans-8,9-dihydrodiol > 6-MBA > 6-MBA trans-10,11-dihydrodiol > 4-hydroxy-6-MBA 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.

¹ This work was supported by USPHS grant CA29133. The experiments reported herein were conducted according to the principles set forth in the Guide for the Care and Use of Laboratory Animals, Institute of Animal Resources, National Research Council, Department of Health, Education, and Welfare Publication (NIH) 78-23. A preliminary report of this work has appeared (1).

² To whom requests for reprints should be addressed.

Received 2/19/85. Revised 5/23/85. Accepted 6/ 3/85.