title: 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 (32)P-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.
authors.affiliation: Department of Environmental Science and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Swartz
authors.forename: Leon C
authors.initials: LC
authors.lastname: King
authors.forename: Stephen
authors.initials: S
authors.lastname: Nesnow
authors.forename: David M
authors.initials: DM
authors.lastname: Umbach
authors.forename: Subodh
authors.initials: S
authors.lastname: Kumar
authors.forename: Harish
authors.initials: H
authors.lastname: Sikka
authors.forename: David M
authors.initials: DM
authors.lastname: Demarini
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D018736:DNA Adducts / Q000096:biosynthesis*; D004269:DNA, Bacterial / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity; D010616:Phenanthrenes / Q000737:chemistry / Q000633:toxicity*; D012475:Salmonella / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000633:toxicity*
chemical_list: D018736:DNA Adducts; D004269:DNA, Bacterial; D009153:Mutagens; D010616:Phenanthrenes; D013876:Thiophenes; C002615:benzo(c)phenanthrene