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MUTATION SPECTRUM OF CIGARETTE SMOKE CONDENSATE IN SALMONELLA: COMPARISON TO MUTATIONS IN SMOKING-ASSOCIATED TUMORS
Citation:
DeMarini, D.M., M. Shelton, AND J. Levine. MUTATION SPECTRUM OF CIGARETTE SMOKE CONDENSATE IN SALMONELLA: COMPARISON TO MUTATIONS IN SMOKING-ASSOCIATED TUMORS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/548.
Description:
We used colony probe hybridization and polymerase chain reaction/DNA sequence analysis to determine the mutations in 1,600 revertants of salmonella induced by cigarette smoke condensate (CSC) in the presence of S9.CSC induced 80% G.C T-A transversions and 20% G.C A-T transitions at the base-substitution allele (hisG46) in strain TA100. his spectrum was similar to those of the polycyclic aromatic hydrocarbon (PAH) benzo[a)pyrene (BAP) and various aromatic amines such as 4-aminobiphenyl (4AB) and Glu-P-1, all of which are present in CSC. his spectrum was also similar to that produced by PAHs in other bacteria, mammalian cells, and rodents as well as to that of the p53 gene in lung tumors from smokers. aboratory studies in rodents have indicated that PAHB in cigarette smoke play an important role in smoking-associated lung cancer. he results in Salmonella support a role for the PAH component of cigarette smoke in the base-substitution specificity found in the p53 gene of smoking-associated lung tumors. t the frameshift allele in strains TA1538 and TA98, CSC induced only a hotspot 2-base deletion, which is a mutation spectrum that is identical to that induced by the heterocyclic amine pyrolysate products of amino acids, such as Glu-P-1. his is consistent with bioassay-directed fractionation studies showing that aromatic amines account for most of the frameshift specificity of CSC in Salmonella. odent and human studies indicate that aromatic amines are responsible for smoking-associated bladder cancer. lthough no gene has been found that is mutated in a majority of bladder tumors, the present study would suggest that when found, such a gene might exhibit a mutation spectrum reflective of aromatic amine mutagenesis, i.e., primarily G.C T-A transversions and frameshifts. his study (1) confirms our previous studies showing that the mutation spectrum of a complex mixture reflects the dominance of particular classes of chemical mutagens within the mixture, and (2) illustrates the potential of bioassay-directed molecular analysis for identifying the chemical classes in a complex mixture that are responsible for specific classes of mutation and tumor types produced by the mixture.