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Influence of polymorphisms in xenobiotic‐metabolizing genes and DNA‐repair genes on diepoxybutane‐induced SCE frequency
Author(s) -
Laczmanska Izabela,
Gil Justyna,
Karpinski Pawel,
Stembalska Agnieszka,
Kozlowska Joanna,
Busza Halina,
Trusewicz Alicja,
Pesz Karolina,
Ramsey David,
SchladeBartusiak Kamila,
Blin Nikolaus,
Sasiadek Maria Malgorzata
Publication year - 2006
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20253
Subject(s) - xrcc3 , gene , genetics , biology , dna repair , xenobiotic , dna damage , dna , mutagen , microbiology and biotechnology , genotype , single nucleotide polymorphism , enzyme , biochemistry
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 (X RCC1, 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. Environ. Mol. Mutagen. 47:, 2006. © 2006 Wiley‐Liss, Inc.