MODULATION OF DNA ADDUCT LEVELS IN HUMAN MONONUCLEAR WHITE BLOOD-CELLS AND GRANULOCYTES BY CYP1A1, CYP2D6 AND GSTM1 GENETIC POLYMORPHISMS

The CYP1A1, CYP2D6 and GSTM1 genes encode biotransforming enzymes invo lved in activation and detoxification of xenobiotics. Metabolically ac tivated chemical compounds may interact with DNA and form adducts, In this study, the effect of the GSTM1, CYP1A1 exon 7 and CYP2D6 polymorp hisms on DNA adduct levels was studied in 170 healthy volunteers. DNA adducts levels were measured by P-32-postlabelling in mononuclear whit e blood cells (WBC, lymphocytes and monocytes) and granulocytes collec ted in summer and winter. The influence of the genotype on the level o f DNA adducts in both types of WBCs was observed only in summer sample s. Individuals with GSTM1 deficient (null) genotype had significantly elevated level of adducts in mononuclear WBCs (p = 0.045) and granuloc ytes (p = 0.031) compared to GSTM1 positives. Higher adduct levels in carriers of combined GSTM1(null)/CYP1A1-Ile/Val genotype were found in both types of WBCs when compared to GSTM1(+)/CYP1A1-Ile/Ile genotype carriers (p = 0.046 in granulocytes, p = 0.092 in mononuclear WBCs). C YP2D6 wild-type homozygotes (EMs) and heterozygotes (HEMs) were shown to have significantly higher mononuclear WBC DNA adduct levels than mu tant homozygotes (PMs) (p = 0.037 and p = 0.014). When confounding fac tors associated with PAH exposure were taken into account a statistica lly significant effect of CYP1A1 exon 7 polymorphism on DNA adduct lev els was found (p = 0.012 in mononuclear WBCs, p = 0.043 in granulocyte s). In a subgroup of current smokers (n = 95) high DNA adduct levels i n granulocytes were associated with GSTM1(null) genotype, and increase d adduct levels in mononuclear WBCs correlated with CYP2D6 EM and HEM genotypes. In winter samples the association between the genotype and DNA adduct levels was not observed. (C) 1998 Elsevier Science B.V. All rights reserved.