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Metabolic Activation of Dibenzo(a,h)anthracene and Its Dihydrodiols to Bacterial Mutagens

Department of Biochemistry and Drug Metabolism, Hoffmann-LaRoche Inc., Nutley, New Jersey 07110 [A. W. W., W. L., P. E. T., D. R., A. H. C.], and Section on Oxidation Mechanisms, Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, NIH, Bethesda, Maryland 20014 [J. M. K., H. Y., D. M. J.]

Dibenzo(a,h)anthracene and the three metabolically possible trans-dihydrodiols of dibenzo(a,h)anthracene were tested for mutagenicity toward Salmonella typhimurium strain TA 100 in the presence of hepatic microsomes from Aroclor 1254-pretreated rats or the cytochrome P-450-dependent monooxygenase system isolated and purified to near homogeneity from these microsomes. With either enzyme system trans-3,4-dihydroxy-3,4-dihydrodibenzo(a,h)anthracene was activated to products that were more mutagenic to the bacteria than were the metabolites of dibenzo(a,h)anthracene or the metabolites of the 1,2-and 5,6-dihydrodiols of dibenzo(a,h)anthracene. With microsomes but not with the purified monooxygenase system, trans-5,6-dihydroxy-5,6-dihydrodibenzo(a,h)anthracene was also activated to products that were highly mutagenic to the bacteria. However, significant activation was seen only when high concentrations of trans-5,6-dihydroxy-5,6-dihydrodibenzo(a,h)anthracene were incubated with relatively high amounts of enzyme. Saturation of the double bond at position 1,2 of trans-3,4-dihydroxy-3,4-dihydrodibenzo(a,h)anthracene produced a tetrahydrodiol that was poorly activated in the presence of either microsomes or the purified monooxygenase system. The high activity of trans-3,4-dihydroxy-3,4-dihydrodibenzo(a,h)anthracene in both metabolic activation systems and the importance of the double bond in 1,2-position of the dihydrodiol strongly suggest that a bay-region 3,4-diol-1,2-epoxide is a biologically important active metabolite of dibenzo(a,h)anthracene, thereby providing support for the bay region theory.

¹ To whom requests for reprints should be addressed.

² Recipient of National Cancer Institute Grant 1 F32 CA05729-01.

Received 12/27/77. Accepted 4/ 4/78.

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