title: Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency.
abstract: Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.
authors.affiliation: Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Laczmanska
authors.forename: Justyna
authors.initials: J
authors.lastname: Gil
authors.forename: Pawel
authors.initials: P
authors.lastname: Karpinski
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Stembalska
authors.forename: Joanna
authors.initials: J
authors.lastname: Kozlowska
authors.forename: Halina
authors.initials: H
authors.lastname: Busza
authors.forename: Alicja
authors.initials: A
authors.lastname: Trusewicz
authors.forename: Karolina
authors.initials: K
authors.lastname: Pesz
authors.forename: David
authors.initials: D
authors.lastname: Ramsey
authors.forename: Kamila
authors.initials: K
authors.lastname: Schlade-Bartusiak
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Blin
authors.forename: Maria Malgorzata
authors.initials: MM
authors.lastname: Sasiadek
mesh_terms: D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics; D004852:Epoxy Compounds / Q000633:toxicity*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D011110:Polymorphism, Genetic; D012854:Sister Chromatid Exchange; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity
chemical_list: D004268:DNA-Binding Proteins; D004852:Epoxy Compounds; D009153:Mutagens; D015262:Xenobiotics; C007366:diepoxybutane; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases