To study the potential links between genetic polymorphisms in the GSTT1, GSTM1, GSTP1 genes and the frequency of chromosomal aberrations (CAs) in lung cancer patients and healthy residents in Russian Federation.
This study was conducted to determine the association between arsenic exposure and polymorphisms of genes involved in detoxification (glutathione S-transferase T1 [GSTT1], glutathione S-transferase M1 [GSTM1], glutathione S-transferase O2 [GSTO2], catalase [CAT], and NAD(P)H quinone oxidoreductase1 [NQO1]) as well as nonhomologous end joining DNA repair genes (XRCC4, XRCC5, and XRCC6) with induction of chromosomal aberrations.
We performed the analysis of CA by trypsin G-banding, micronucleus (MN) assay, Comet assay and Xenobiotic-metabolizing gene polymorphisms (GSTM1, GSTT1 and GSTP1) in 56 exposed and 56 control subjects who were matched for gender and age (± 2 years).
Both DNA adduct levels and chromosomal aberrations were tested for correlation with lifestyle and the polymorphisms of cytochromes P450 CYP1A1 and CYP1B1 as well as glutathione-S-transferases GSTM1 and GSTT1.
Combined analysis of chromosomal aberrations and glutathione S-transferase M1 and T1 polymorphisms in pathologists occupationally exposed to formaldehyde.
Individuals with null GSTM1, GSTT1, and GSTP1 (val/val) showed inhibition of mitotic index (MI) and significant (p < 0.01) induction of CA as compared to individuals with GSTM1, GSTT1, and GSTP1 (ile/ile).
The CA frequency in exposed workers was influenced by the polymorphic genotypes: GSTM1 null (RR 1.33, 95% CI 1.31-1.69, p<0.001), XRCC1(194) Arg/Trp, Trp/Trp (RR 1.23, 95% CI 1.08-1.40, p<0.001) and by the wild genotypes CYP2E1 C1/C1 (RR 1.20, 95% CI 1.05-1.37, p<0.001), GSTT1 positive (RR 1.49, 95% CI 1.31-1.69, p<0.001), XRCC1(280) Arg/Arg (RR 1.44, 95% CI 1.26-1.64, p<0.001) and XRCC1(241) Thr/Thr (RR 1.54, 95% CI 1.34-1.76, p=0.001).
To evaluate the role of polymorphisms in glutathione S-transferase (GST) M1 (GSTM1) and theta 1 (GSTT1) as effect modifiers of the association between CA and cancer risk.
The initial study found that urine concentrations of the metabolites 1,2-dihydroxy-4-(acetyl) butane (M1) and 1-dihydroxy-2-(N-acetylcysteinyl)-3-butene (M2) and blood concentrations of the hemoglobin adducts N-[2-hydroxy-3-butenyl] valine (HB-Val) and N-[2,3,4-trihydroxy-butyl] valine (THB-Val) constitute excellent biomarkers of exposure, both being highly correlated with BD exposure levels, and that GST genotypes modulate at least one metabolic pathway, but that irreversible genotoxic effects such as chromosome aberrations and HPRT gene mutations are neither associated with BD exposure levels nor with worker genotypes (GST [glutathione-S-transferase]-M1, GSTT1, CYP2E1 (5' promoter), CYP2E1 (intron 6), EH [epoxide hydrolase] 113, EH139, ADH [alcohol dehydrogenase]2 and ADH3).
We found a significant increase of chromosome aberrations in patients and controls that had the XPD 751Gln and GSTM1 null genotypes, indicating a mechanistic causation of the disease.
In the present study, we investigated markers of genotoxicity [chromosomal aberrations (CAs) and single-strand breaks (SSBs)] in a cohort of 110 tire plant workers engaged in jobs with different levels of xenobiotic exposure in relation to various polymorphisms in genes coding for biotransformation enzymes (CYP1A1, CYP2E1, EPHX1, GSTM1, GSTP1, and GSTT1) and in genes involved in DNA repair (XPD exon 23, XPG exon 15, XPC exon 15, XRCC1 exon 10, and XRCC3 exon 7).
The lack of glutathione S-transferase M1 (GSTM1 null genotype) is associated with increased sensitivity to genotoxicity of tobacco smoke, and GSTM1 null smokers also show an increased frequency of CAs and SCEs.
We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05).
For example, the presence of the GSTM1 null genotype (GSTM1 0/0) is responsible for the highest level and significant induction of CA, irrespective of the presence of other genotypes in the different donors.
Also, no significant differences between the two groups of individuals (GSTM1 positive and GSTM1 null) were observed for BLM-induced chromosomal aberrations.
Individuals with a decreased rate of detoxification, i.e., lacking the glutathione S-transferase M1 gene, have a slightly higher level of bulky carcinogen-DNA adduct in some tissues, and do also have an increased level of chromosomal aberrations.
The effect of the GSTM1 genotype, which was observed only in the bus drivers, appears to be associated with air pollution, whereas the NAT2 genotype effect, which affected all subjects, may influence the individual response to some other common exposure or the baseline level of chromosomal aberrations.
Cytogenetic markers (chromosomal aberrations, sister chromatid exchanges (SCE), cells with high frequency of SCE (HFC), the heterogeneity index SCE (SCE-H) and genetic polymorphism of genotypes GSTM1 and NAT2 were evaluated in the peripheral lymphocytes of 64 coke oven workers and 34 control subjects from the same plant.
Despite the limited number of subjects genotyped, the results seem to indicate an association between smoking induced CA frequencies and GSTM1 polymorphism, and a possible interaction between the GSTM1 and GSTT1 genotypes.
Chromosomal aberrations (gaps excluded) were significantly (P < 0.05) increased among the workers lacking the GSTT1 gene as compared to the BD workers with the gene, while the other polymorphic GSTM1 gene showed no association with the cytogenetic parameters.
In addition, a possible interaction was observed between smoking and GSTM1 genotype in the CA assay, GSTM1 null smokers, earlier reported to have an elevated risk for lung cancer, showing higher CA frequencies than GSTM1 positive smokers.