Variant metabolizing gene alleles determine the genotoxicity of benzo[a]pyrene

Understanding the mechanisms involved with genetic susceptibility to environmental disease is of major interest to the scientific community. We have conducted an in vitro study to elucidate the involvement of polymorphic metabolizing genes on the genotoxicity of benzo[a]pyrene (BP). Blood samples from 38 donors were treated with BP and the induction of sister chromatid exchanges (SCE) and chromosome aberrations (CA) were evaluated. The latter is based on the tandem-probe fluorescence in situ hybridization (FISH) assay. The data indicate that the induction of genotoxicity was clearly determined by the inherited variant genotypes for glutathione-S-transferase (GSTM1) and microsomal epoxide hydrolase (EH). In a comparison of the two biomarkers, the CA biomarker shows a more definite association with the genotypes than does SCE. For example, the presence of the GSTM1 null genotype (GSTM1 0/0) is responsible for the highest level and significant induction of CA, irrespective of the presence of other genotypes in the different donors. This effect is further enhanced significantly by the presence of the excessive activation EH gene allele (EH4*) and decreased by the reduced activation EH gene allele (EH3*). Overall, the modulation of genotoxicity by the susceptibility genotypes provides support of their potential involvement in environmental cancer. Furthermore, the data indicate that the variant enzymes function independently by contributing their metabolic capability toward the expression of biologic activities. Therefore, studies like this one can be used to resolve the complexity of genetic susceptibility to environmental disease in human.