Mutagenic activity of the 4,5- and 9,10-dihydrodiols of benzo[J]fluoranthene and their syn- and anti-dihydrodiol epoxides in salmonella typhimurium

The objective of this study was to determine the relative mutagenic activities of the major dihydrodiol metabolites of benzoj]fluoranthene (Bj]F) and their corresponding syn- and anti-dihydrodiol epoxides. Salmonella typhimurium tester strains TA97a, TA98, and TA100 were used to evaluate the mutagenic potencies of the parent hydrocarbon and these suspect proximate and ultimate mutagenic metabolites. Bj]F and the trans-dihydrodiol metabolites were active only in the presence of an external metabolic activation system (S9) with the exception of the Bj]F-4,5-diol, which was weakly active in TA98 and TA100 in the absence of S9. The Bj]F-4,5-diol was more mutagenic than the Bj]F-9,10-diol in tester strains TA98 and TA100, whereas the opposite effect was observed in TA97a. In the absence of S9, the anti-Bj]F-4,5-diol epoxide was more mutagenic than the syn-Bj]F-4,5-diol epoxide and the syn- and anti-Bj]F-9,10-diol epoxides in tester strains TA97a and TA100. The exceptional mutagenic potency of the anti-Bj]F-4,5-diol epoxide in TA100 resembles that observed by epoxides located within a fjord, or by the anti-diol epoxides of bay region methylated polycyclic aromatic hydrocarbons. In contrast, the mutagenicity of the pseudo bay region dihydrodiol epoxides arising from the Bj]F-9,10-diol more closely resembles that observed with the classical bay region dihydrodiol epoxides of chrysene. In summary, both dihydrodiol metabolites of Bj]F are mutagenic in S. typhimurium, and the relative potency varies among the tester strains. The highest mutagenic response was achieved in tester strain TA100, which detects base-pair substitutions. The most potent direct-acting dihydrodiol epoxide in this tester strain was the anti-Bj]F-4,5-diol epoxide, which agrees with the results of mouse skin painting studies that indicate that the Bj]F-4,5-diol is more tumorigenic that the parent hydrocarbon or the Bj]F-9,10-diol. A cova-lent DNA adduct formed between the anti-Bj]F-4,5-diol epoxide and deoxyguanosine was the major species of DNA adduct formed in S. typhimurium. This adduct corresponds to the major DNA adduct formed in mouse skin following application Bj]F.