title: Genetic polymorphisms and possible gene-gene interactions in metabolic and DNA repair genes: effects on DNA damage.
abstract: We investigated in a central European population, the association between genetic polymorphisms in several genes coding for xenobiotic metabolizing enzymes (CYP1A1, CYP2E1, EPHX1, GSTP1, GSTM1 and GSTT1) and in DNA repair genes (XPD, XPG, XPC and XRCC1) and the levels of single-strand breaks (SSBs) and SSB endonuclease III sensitive sites (endoIII sites) in peripheral blood lymphocytes. No significant differences in the mean levels of SSBs and endoIII sites after stratification for main confounders and occupational exposure were observed in the studied population. Significantly higher levels of SSBs were observed in individuals bearing the wild-type alleles (AA) (0.75+/-0.51SSB/10(9)Da) and heterozygous (AC) genotypes (0.67+/-0.49SSB/10(9)Da) compared to those with homozygous XPD (CC) genotype (0.43+/-0.28SSB/10(9)Da, P=0.033). A moderate increase in the levels of SSBs was also found in individuals with the homozygous XPG exon 15 wild type (GG) and heterozygous (GC) genotypes in comparison to those with the homozygous (CC) genotype (P=0.066) and in individuals with low activity EPHX1 genotype in comparison to those with high activity genotype. Nevertheless, these differences were not statistically significant. No other significant association was found. When gene-gene interactions were evaluated, a combination of EPHX1 activity genotypes with that of either XPD or XPG significantly (P=0.003 and 0.016, respectively) modulated SSB levels resulting in a three-fold difference between the "protective" and the "adverse" genotype-combinations. Almost three-fold differences in SSB levels were found between the "protective" and the "adverse" genotype-combinations of EPHX1 activity genotype and GSTM1 or GSTT1 genotypes, respectively. In conclusion, our results suggest a relation between markers of genotoxicity and polymorphisms in genes coding for xenobiotic metabolizing and DNA repair enzymes as well as a modulating effect of combinations of these polymorphisms.
authors.affiliation: Inst. Exper. Medicine, Acad. Sci. of the Czech Republic, Videnska 1083, 14200 Prague 4, Czech Republic.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.forename: Pavel
authors.initials: P
authors.lastname: Soucek
authors.forename: Rudolf
authors.initials: R
authors.lastname: Stetina
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.forename: Katerina
authors.initials: K
authors.lastname: Trtkova
authors.forename: Maria
authors.initials: M
authors.lastname: Dusinska
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
mesh_terms: D000328:Adult; D015415:Biomarkers; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D015415:Biomarkers