Association of Polymorphisms in AhR, CYP1A1, GSTM1, and GSTT1 Genes with Levels of DNA Damage in Peripheral Blood Lymphocytes among Coke-Oven Workers

Abstract

Accumulating evidence has shown that both DNA damage caused by the metabolites of polycyclic aromatic hydrocarbons (PAH) and genetic polymorphisms in PAH-metabolic genes contribute to individual susceptibility to PAH-induced carcinogenesis. However, the functional relevance of genetic polymorphisms in PAH-metabolic genes in exposed individuals is still unclear. In this study of 240 coke-oven workers (the exposed group) and 123 non -coke-oven workers (the control group), we genotyped for polymorphisms in the AhR, CYP1A1, GSTM1, and GSTT1 genes by PCR methods, and determined the levels of DNA damage in peripheral blood lymphocytes using the alkaline comet assay. We found that the ln-transformed Olive tail moment (Olive TM) values in the exposed group were significantly higher than those in the control group (P < 0.001). Furthermore, in the exposed group, the Olive TM values in subjects with the AhR Lys 554 variant genotype were higher than those with the AhR Arg 554 /Arg 554 genotype (P = 0.021). Similarly, the Olive TM values in the non -coke-oven workers with the CYP1A1 MspI CC + CT genotype were lower than the values of those with the CYP1A1 MspI TT genotype (P = 0.005). However, these differences were not evident for GSTM1 and GSTT1. These results suggested that the polymorphism of AhR might modulate the effects of PAHs in the exposed group; however, the underlying molecular mechanisms by which this polymorphism may have affected the levels of PAH-induced DNA damage warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1703 -7)

Impact of AhR, CYP1A1 and GSTM1 Genetic Polymorphisms on TP53 R273G Mutations in Individuals Exposed to Polycyclic Aromatic Hydrocarbons

“…Further, the metabolism of PAHs induces DNA damage and carcinogenesis which could be modulated by genetic variation (Shimizu et al, 2000;Jiang et al, 2005;Ramadoss et al, 2005;Chen et al, 2006). In this study, significant difference (p=0.02, 95%CI, 0.70-15.86) was observed in the R273G mutation in p53 exon 8 for the genetic polymorphisms of Lys/Arg for AhR.…”

“…CYP1A1 is the most potently induced gene following AHR activation. The homozygous deletion of GSTM1 leads to the loss of GSTM1 functions (Nerurkar et al, 2000;Chen et al, 2006;Moretti et al, 2007). Therefore, the results indicated that the functions of AhR, CYP1A1 and GSTM1 were more impaired or modified with higher PAH exposure.…”

“…The polymorphism of CYP1A1(BseMI) of TgC transition is located downstream of exon7 (m2 polymorphism). This polymorphism results in a substitution of a isoleucine (Ile) for a valine (val) mutation at amino acid residue 462 in the heme binding region of CYP1A1 protein (Chen et al, 2006;Giri et al, 2012). GST is a multigene family which includes five subgroups (i.e., α, π, μ,τ and ζ).…”

“…Generally, GSTM1 can detoxify reactive metabolites of benzo(a)pyrene and other PAHs (Smart and Daly, 2000;Chen et al, 2006;Giri et al, 2012). Here, we found that the frequency of variants in the AhR Lys 554 and CYP1A1 val variant genotype and GSTM1 null genotype showed slight higher in exposed group (63.7%, 62.8%, 58.4%, respectively) than in control subjects (59.8%, 61.0%, 57.3%, respectively) on urinary 1-OHP excretion, though did not show significant differences.…”

CYP1A1 Gene Polymorphisms: Modulator of Genetic Damage in Coal-Tar Workers

“…Therefore, it is reasonable to hypothesize that genetic polymorphisms of CYP1A1 may play a role in individual susceptibility to genetic damage and developing various types of cancers. The CYP1A1 gene polymorphisms were examined extensively to evaluate the possible role they play in DNA damage and cancer promotion in PAHs exposed populations (Chen et al, 2006;Moretti et al, 2007). Coal-tar workers, working at coal-tar melting and road construction sites, are poorly characterized regarding the CYP1A1 gene polymorphisms as a modulator of genetic damage.…”