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.

Drug metabolising enzyme polymorphisms in Middle- and Eastern-European Slavic populations

“…A study focused on Brought to you by | University of Queensland -UQ Library Authenticated Download Date | 6/14/15 12:22 PM the analysis of alcoholic pancreatitis [9] that reported < 1% of patients were carriers of the minor C2 allele, and an independent healthy group has found slightly more than 5% of C2 allele carriers [8] These studies contrast with a third study [10], reporting a much higher frequency of carriers of this allele in healthy individuals (17%). Such high frequencies contradict published results from other populations as well as unpublished results from neighbouring Czech populations (Hubacek, unpublished results), which are in agreement with the first studies.…”

Polymorphism in nucleotide excision repair gene XPC correlates with bleomycin‐induced chromosomal aberrations

“…Polymorphisms in DNA repair, as well as XME genes were determined as previously described [Laczmanska et al, 2006]. PCR products were separated on 2% agarose gels, stained with ethidium bromide and directly visualized by UV illumination.…”

CYP1A1 Ile462Val polymorphism and colorectal cancer risk in Polish patients

“…Genotyping of studied polymorphisms was performed using polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP) method described elsewhere [8, 16]. …”

“…Xenobiotic-metabolizing enzymes (XMEs) create a first line of protection against numerous mutagenic agents [8]. An activation of chemical pro-carcinogens is mediated mainly by cytochrome P-450 enzymes (phase I biometabolism of xenobiotics), while an elimination of environmental chemicals proceeds through the complex detoxification mechanisms and is associated with phase II biometabolic enzymes [9].…”