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

Understanding the mechanisms involved with genetic susceptibility to enviro nmental disease is of major interest to the scientific community. We have c onducted an in vitro study to elucidate the involvement of polymorphic meta bolizing genes on the genotoxicity of benzo[a]pyrene (BP). Blood samples fr om 38 donors were treated with BP and the induction of sister chromatid exc hanges (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) a nd microsomal epoxide hydrolase (EH). In a comparison of the two biomarkers , the CA biomarker shows a more definite association with the genotypes tha n 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, irr espective of the presence of other genotypes in the different donors. This effect is further enhanced significantly by the presence of the excessive a ctivation EH gene allele (EH4*) and decreased by the reduced activation EH gene allele (EH3*). Overall, the modulation of genotoxicity by the suscepti bility genotypes provides support of their potential involvement in environ mental cancer. Furthermore, the data indicate that the variant enzymes func tion independently by contributing their metabolic capability toward the ex pression of biologic activities. Therefore, studies like this one can be us ed to resolve the complexity of genetic susceptibility to environmental dis ease in human. (C) 2001 Wiley-Liss, Inc.