Mutagenicity, stable DNA adducts, and abasic sites induced in Salmonella by phenanthro[3,4- b]- and phenanthro[4,3- b]thiophenes, sulfur analogs of benzo[ c]phenanthrene

Abstract

Sulfur-containing polycyclic aromatic hydrocarbons (thia-PAHs or thiaarenes) are common constituents of air pollution and cigarette smoke, but only a few have been studied for health effects. We evaluated the mutagenicity in Salmonella TA98, TA100, and TA104 of two sulfur-containing derivatives of benzo[ c]phenanthrene, phenanthro[3,4- b]thiophene (P[3,4- b]T), and phenanthro[4,3- b]thiophene (P[4,3- b]T) as well as their dihydrodiol and sulfone derivatives. In addition, we assessed levels of stable DNA adducts (by 32P-postlabeling) as well as abasic sites (by an aldehydic-site assay) produced by six of these compounds in TA100. P[3,4- b]T and its 6,7- and 8,9-diols, P[3,4- b]T sulfone, P[4,3- b]T, and its 8,9-diol were mutagenic in TA100. P[3,4- b]T sulfone, the most potent mutagen, was approximately twice as potent as benzo[ a]pyrene in both TA98 and TA100. Benzo-ring dihydrodiols were much more potent than K-region dihydrodiols, which had little or no mutagenic activity in any strain. P[3,4- b]T sulfone produced abasic sites and not stable DNA adducts; the other five compounds examined, B[ c]P, B[ c]P 3,4-diol, P[3,4- b]T, P[3,4- b]T 8,9-diol, and P[4,3- b]T 8,9-diol, produced only stable DNA adducts. P[3,4- b]T sulfone was the only compound that produced significant levels of frameshift mutagenicity and induced mutations primarily at GC sites. In contrast, B[ c]P, its 3,4-diol, and the 8,9 diols of the phenanthrothiophenes induced mutations primarily at AT sites. P[3,4 -b]T was not mutagenic in TA104, whereas P[3,4- b]T sulfone was. The two isomeric forms (P[3,4- b]T and P[4,3- b]T) are apparently activated differently, with the latter, but not the former, involving a diol pathway. This study is the first illustrating the potential importance of abasic sites in the mutagenicity of thia-PAHs.