Spectrum of spontaneous and 2,4,6-trinitrotoluene (TNT)-induced mutations in Salmonella typhimurium strains with different nitroreductase and O-acetyltransferase activities.

Spontaneous and 2,4,6-trinitrotoluene (TNT)-induced mutation spectra were determined at the hisD3052 allele of Salmonella typhimurium strains TA98, YG1021 (nitroreductase-overproducing) and YG1024 (O-acetyltransferase-overproducing). In TA98, 55% (11/20) of the spontaneous reversions and 95% (19/20) of reversions in TNT-treated plates were deletions of two bases at the same site (-2 hotspot deletions), whereas the respective figures were 65% (13/20) and 80% (16/20) in YG1021, and 75% (15/20) and 95% (19/20) in YG1024. Other mutations observed in the TNT treatment were complex frameshifts consisting of either a -2 hotspot deletion and a base substitution, or a +1 addition and base substitution at the stop codon. In addition, different kinds of deletions were recovered in the spontaneous spectra. The elevated enzymatic activities of strains, YG1021 and YG1024, resulting in enhanced mutagenicity of TNT, did not seem to have an effect on the spectrum of TNT-induced mutations. However, the YG strains, which also have a higher spontaneous revertant yield than the parental strain TA98, seemed to differ from TA98 in their spontaneous spectra. The increase consisted of revertants containing the -2 hotspot deletion, possibly indicating elevated activation of exogenous or endogenous premutagens by the higher enzyme activities of the YG strains.

Modulation of urinary mutagenicity by genetically determined carcinogen metabolism in smokers.

We examined the genotypes of two polymorphic genes involved in the detoxification of several mutagenic and carcinogenic compounds in relation to tobacco smoking-associated urinary mutagenicity. The genes studied were the glutathione S-transferase-encoding GSTM1 gene and acetyltransferase-encoding NAT2 gene. Smokers with no GSTM1 gene (n = 7) had urine that was several times more mutagenic than that of smokers with the gene (n = 10). The mean level of urinary mutagenicity in presence of metabolic activation was 2527 +/- 958 revertants/100 ml urine for GSTM1-smokers compared to 766 +/- 560 revertants/100 ml for GSTM1+ smokers (P < 0.001) using the bacterial strain YG1024. The corresponding values using the TA98 strain were 336 +/- 124 and 123 +/- 75 (P < 0.001). In contrast, we failed to show any difference in the level of urinary mutagenicity between slow-acetylator and fast-acetylator NAT2 genotypes among smokers (n = 17) or non-smokers (n = 35). Our results offer one explanation for the recent findings that GSTM1 polymorphism is a risk modifier in smoking-related cancers, especially bladder cancer.