title: Rat hepatocyte-mediated bacterial mutagenicity in relation to the carcinogenic potency of benz(a)anthracene, benzo(a)pyrene, and twenty-five methylated derivatives.
abstract: 7,12-Dimethylbenz(a)anthracene, benz(a)anthracene, and benzo(a)pyrene as well as the 24 monomethylbenzo(a)pyrenes (MBPs) and monomethylbenz(a)anthracenes (MBAs), compounds which differ in carcinogenicity from very potent to apparently inactive, were investigated for mutagenicity (reversion to histidine prototrophy) in Salmonella typhimurium TA100 using either intact or NADPH-fortified homogenized rat hepatocytes for metabolic activation. In both systems, all 27 hydrocarbons showed positive responses. Their mutagenic potency in the homogenate-mediated test varied in a narrow range and did not correlate detectably with their reported activity in carcinogenicity experiments. When the cell homogenate was replaced by intact cells, the maximal mutagenic effects were weaker by factors of 1 to 14, depending on the compound, and were seen only at higher substrate concentrations. The differences between cell- and homogenate-mediated mutagenicity were small with the strong carcinogens 7,12-dimethylbenz(a)anthracene 7-MBA, 12-MBA, benzo(a)pyrene, 1-MBP, and 11-MBP. The differences were large with the apparent noncarcinogens and those weak carcinogens that were strongly mutagenic in the homogenate-mediated test. As a result of this differential reduction in activity, the cell-mediated mutagenicity did not correlate with the homogenate-mediated mutagenicity but correlated approximately with the carcinogenic potency. The lowest effects in the cell-mediated experiments were seen with 7-, 8-, 9- and 10-MBP, 2-MBA, and 3-MBA. In these compounds, the methyl group is attached to a carbon of the terminal angular benzo ring, and therefore bay-region diol-epoxides, if formed at all, additionally would carry a methyl group on one of the oxidized positions. On the other hand, among all the compounds tested 7,12-dimethylbenz(a)anthracene, 12-MBA, and 11-MBP, which have the methyl group attached in the bay-region position opposite the terminal benzo ring, showed the highest mutagenic efficacies in the cell-mediated test, as compared to those observed in the homogenate-mediated test. These structure-activity relationships and the previously reported observation that among various promutagenic benzo(a)pyrene metabolites only the 7,8-dihydrodiol was strongly mutagenic in the cell-mediated test would suggest that in the cell-mediated bacterial mutagenicity test, bay-region diol-epoxides are the ultimate mutagens which are preferentially detected.
mesh_terms: D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001711:Biotransformation; D002273:Carcinogens; D008099:Liver / Q000378:metabolism*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D001551:Benz(a)Anthracenes; D002273:Carcinogens; D009153:Mutagens; D001564:Benzo(a)pyrene; C030935:benz(a)anthracene