Metabolic activation of 3-methylcholanthrene and its metabolites to products mutagenic to bacterial and mammalian cells.

3-Methylcholanthrene and six of its metabolites were tested for their ability to be metabolized by either hepatic microsomes from Aroclor 1254-pretreated rats or a puri fied hepatic cytochrome P-450-dependent monooxygenase system to products mutagenic to bacterial and mam malian cells. When strain TA98 of Salmonella typhimurium was used to detect mutagens and when microsomes were the source of metabolizing enzyme, 1-hydroxy-3-methylchola nth rene was metabolica lly activated to a 10-f o Id-greater extent than was 3-methylcholanthrene and was the most active compound tested. 1,9,10-Trihydroxy-9,10-dihydro3-methylcholanthrene and 3-methylcholanthrene-2-one, the second and third most active compounds, respec tively, were also activated to a greater extent than was 3methylcholanthrene, whereas 2-hydroxy-3-methylcholanthrene was equipotent to the parent hydrocarbon. 3-Methylcholanthrene-1-one was less active than was 3-methyl cholanthrene, and 11,12-dihydroxy-11,12-dihydro-3-methylcholanthrene was inactive. When the highly purified and reconstituted monooxygenase system was the enzyme source, 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene was activated to a 20-fold-greater extent than was 3-methylcholanthrene and was the most active com pound. 3-Methylcholanthrene-2-one and 1-hydroxy-3methylcholanthrene were the second and third most ac tive compounds, respectively. 3-Methylcholanthrene, 3methylcholanthrene-1-one, and 2-hydroxy-3-methylcholanthrene were poorly activated in this system. When strain TA100 of S. typhimurium was used to detect mutations, 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene was metabolically activated to the great est extent by both hepatic microsomes and the purified monooxygenase system. The metabolites formed from this compound were 15 and 100 times more mutagenic than were the metabolites formed from 3-methylcholan threne when the microsomes and the purified monooxy genase system, respectively, were the enzyme source. 3Methylcholanthrene-2-one was the second most active substrate with either enzyme system. Although 3-methylcholanthrene-1-one was the third most active substrate in the presence of microsomes, it was the least active substrate in the presence of the purified enzyme system. 1-Hydroxy-3-methylcholanthrene, the third most active 1To whom requests for reprints should be addressed. ' Recipient of National Cancer Institute Grant CA 21481. Received May 15, 1978; accepted July 18, 1978. substrate in the presence of the purified enzyme system, was the least active of the derivatives when activated by microsomes. 2-Hydroxy-3-methylcholanthrene was poorly metabolized by either enzyme system to products muta genic to strain TA100. When hepatic microsomes from Aroclor 1254-pretreated rats were the source of the monooxygenase activity, the compounds had the same relative mutagenic activities in Chinese hamster V79 cells as they did in strain TA100 of S. typhimurium. 1,9,10-Trihydroxy-9,10-dihydro-3-methylcholanthrene, the most active substrate, was at least 40fold more mutagenic to the mammalian cells than was 3methylcholanthrene. These data indicate that several metabolites of 3-meth ylcholanthrene possess high mutagenic activity after met abolic activation. The expression of their mutagenic activ ity is dependent on the nature of both the metabolic activating system and the target cell with which the mutation is detected. In particular the results show that 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene, the immediate metabolic precursor of a bay-region diol-epoxide, is consistently metabolized to products that are highly mutagenic to bacterial and mammalian cells.