Analyses of bulky DNA adduct levels in human breast tissue and genetic polymorphisms of cytochromes P450 (CYPs), myeloperoxidase (MPO), quinone oxidoreductase (NQO1), and glutathione S-transferases (GSTs)

Abstract

Environmental carcinogens are converted into DNA-reactive metabolites by phase I and phase II enzymes that are involved in the activation and detoxification of xenobiotics. Several of these enzymes display genetic polymorphisms that alter their activity leading to individual variation in DNA damage levels and thus cancer susceptibility. We investigated the relationship between DNA adduct levels and genetic polymorphisms in key enzymes of chemical carcinogenesis: CYP1A1, CYP1A2, GSTT1, GSTM1, GSTP1, NQO1 and MPO. Levels of DNA adducts were determined in human breast tissue using the 32P-postlabeling method. A significantly higher adduct level was observed for individuals with the A-463 variant in the MPO gene (P=0.008), providing the first observation of an association between a predicted reduced MPO gene transcription and a higher level of DNA adducts. Furthermore, levels of DNA adducts were about 45% higher in individuals with either GSTP1*B or GSTP1*C variants compared to those homozygous for the wild-type allele. When the MPO and GSTP1 were examined together, individuals with these combined variant genotypes had significantly higher adduct levels than all other genotype combinations (P=0.003).