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

  • Gao, Meili ;
  • Li, Yongfei ;
  • Xue, Xiaochang ;
  • Long, Jiangang ;
  • Chen, Lan ;
  • Shah, Walayat ;
  • Kong, Yu
  • Published : 2014.03.30


This study was to undertaken to investigate the impacts of AhR, CYP1A1, GSTM1 genetic polymorphisms on the R273G mutation in exon 8 of the tumor suppressor p53 gene (TP53) among polycyclic aromatic hydrocarbons (PAHs) exposed to coke-oven workers. One hundred thirteen workers exposed to PAH and 82 control workers were recruited. We genotyped for polymorphisms in the AhR, CYP1A1, GSTM1, and TP53 R273G mutation in blood by PCR methods, and determined the levels of 1-hydroxypyrene as PAH exposure marker in urine using the high pressure liquid chromatography assay. We found that the distribution of alcohol users and the urinary excretion of 1-OHP in the exposed workers were significantly higher than that of the control workers (p=0.004, p<0.001, respectively). Significant differences were observed in the p53 genotype distributions of smoking subjects (p=0.01, 95%CI: 1.23-6.01) and PAH exposure (p=0.008, 95%CI: 1.24-4.48), respectively. Further, significant differences were observed in the p53 exon 8 mutations for the genetic polymorphisms of Lys/Arg for AhR (p=0.02, 95%CI: 0.70-15.86), Val/Val for CYP1A1 (p=0.04, 95%CI: 0.98-19.09) and null for GSTM1 (p=0.02, 95%CI: 1.19-6.26), respectively. Our findings indicated that polymorphisms of PAH metabolic genes, such as AhR, CYP1A1, GSTM1 polymorphisms may interact with p53 genetic variants and may contribute to PAH related cancers.



  1. Yao R, Wang Y, D'Agostini F, et al (2005). K-ras mutations in lung tumors from p53 mutant mice exposed to cigarette smoke. Exp Lung Res, 31, 271-81.
  2. van Delft JH, Steenwinkel MS, van Asten JG, et al (2001). Biological monitoring the exposure to polycyclic aromatic hydrocarbons of coke oven workers in relation to smoking and genetic polymorphisms for GSTM1 and GSTT1. Ann Occup Hyg, 45, 395-408.
  3. Wiencke JK, Pemble S, Ketterer B, et al (1995). Gene deletion of glutathione s-transferase theta: correlation with induced genetic damage and potential role in endogenous mutagenesis. Cancer Epidemiol Biomarkers Prev, 4, 253-9.
  4. Yang AL, Smith AG, Akhtar R, et al (1999). Low levels of p53 are associated with resistance to tetrachlorodibenzo-p-dioxin toxicity in DBA/2 mice. Pharmacogenetics, 9, 183-8.
  5. Zhang DS, Lin GF, Ma QW, et al (2002). Nonassociation of aryl hydrocarbon receptor genotypes with susceptibility to bladder cancer in Shanghai population. Acta Pharmacol Sin, 23, 188-92.
  6. Zhong S, Wyllie AH, Barnes D, et al (1993). Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis, 14, 1821-4.
  7. Smart J, Daly AK (2000). Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms. Pharmacogenetics, 10, 11-24.
  8. Shimada T, Fujii-Kuriyama Y (2004). Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1. Cancer Sci, 95, 1-6.
  9. Shimizu Y, Nakatsuru Y, Ichinose M, et al (2000). Benzo[a] pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA, 97, 779-82.
  10. Siwinska E, Mielzynska D, Kapka L (2004). Association between urinary 1-hydroxypyrene and genotoxic effects in coke oven workers. Occup Environ Med, 61, 10.
  11. Smith LE, Denissenko MF, Bennett WP, et al (2000). Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons. J Natl Cancer Inst, 92, 803-11.
  12. Ramadoss P, Marcus C, Perdew GH (2005). Role of the aryl hydro-carbon receptor in drug metabolism. Expert Opin Drug Metab Toxicol, 1, 9-21.
  13. Rusin M, Butkiewicz D, Malusecka E, et al (1999). Molecular epidemiological study of non-small-cell lung cancer from an environmentally polluted region of Poland. Br J Cancer, 80, 1445-52.
  14. Sram RJ, Binkova B (2000). Molecular epidemiology studies on occupational and environmental exposure to mutagens and carcinogens, 1997-1999. Environ Health Perspect, 108, 57-70.
  15. Strickland PT, Kang D, Bowman ED, et al (1994). Identification of 1-hydroxypyrene glucuronide as a major metabolite in human urine by synchronous fluorescence spectroscopy and gas chromatography-mass spectrometry. Carcinogenesis, 15, 483-7.
  16. Nakatsuru Y, Wakabayashi K, Fujii-Kuriyama Y, et al (2004). Dibenzo (A,L) pyrene-induced genotoxic and carcinogenic responses are dramatically suppressed in aryl hydrocarbon receptor-deficient mice. Int J Cancer, 112, 179-83.
  17. Maier A, Micka J, Miller K, et al (1998). Aromatic hydrocarbon receptor polymorphism: development of new methods to correlate genotype with phenotype. Environ Health Perspect, 106, 421-6.
  18. Marczynski B, Rihs HP, Rossbach B, et al (2002). Analysis of 8-oxo-7,8-dihydro-2 -deoxyguanosine and DNA strand breaks in white blood cells of occupationally exposed workers: comparison with ambient monitoring, urinary metabolites and enzyme polymorphisms. Carcinogenesis, 23, 273-81.
  19. Moretti M, Dell'Omo M, Villarini M, et al (2007). Primary DNA damage and genetic polymorphisms for CYP1A1, EPHX and GSTM1 in workers at a graphite electrode manufacturing plant. BMC Public Health, 7, 270.
  20. Nerurkar PV, Okinaka L, Aoki C, et al (2000). CYP1A1, GSTM1, and GSTP1 genetic polymorphisms and urinary 1-hydroxypyrene excretion in non-occupationally exposed individuals. Cancer Epidemiol Biomarkers Prev, 9, 1119-22.
  21. Ovrebo S, Ryberg D, Haugen A, et al (1998). Glutathione S-transferase M1 and P1 genotypes and urinary excretion of 1-hydroxypyrene in coke oven workers. Sci Total Environ, 220, 25-31.
  22. Park JH, Gelhaus S, Vedantam S, et al (2008). The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance. Chem Res Toxicol, 21,1039-49.
  23. Przygodzki RM, Bennett WP, Guinee MD, et al (1998). p53 mutation spectrum in relation to GSTM1, CYP1A1 and CYP2E1 in surgically treated patients with non-small cell lung cancer. Pharmacogenetics, 8, 503-11.
  24. Jongeneelen FJ, Anzion RBM (1990). Analyses of hazardous substances in biological materials. Deutsche Forschungsgemeinschaft, 3, 151-69.
  25. Hussain SP, Amstad P, Raja K, et al (2001). Mutability of p53 hotspot codons to benzo (a) pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung. Cancer Res, 61, 6350-5.
  26. Gu A, Ji G, Jiang T, et al (2012). Contributions of aryl hydrocarbon receptor genetic variants to the risk of glioma and PAH-DNA adducts. Toxicol Sci, 128, 357-64.
  27. Jiang H, Shen YM, Quinn AM, et al (2005). Competingroles of cytochrome P450 1A1/1B1 and aldo-keto reductase 1A1 in the metabolic activation of (+/-)-7, 8-dihydroxy-7,8-dihydrobenzo[ a]pyrene in human bronchoal-veolar cell extracts. Chem Res Toxicol, 18, 365-74.
  28. Hsieh LL, Wang PF, Chen IH, et al (2001). Characteristics of mutations in the p53 gene in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese. Carcinogenesis, 22, 1497-503.
  29. Kawajiri K, Eguchi H, Nakachi K, et al (1996). Association of CYP1A1germ line polymorphisms with mutations of the p53 gene in lung cancer. Cancer Res, 56, 72-6.
  30. Kawajiri K, Watanabe J, Eguchi H, et al (1995). Polymorphisms of human Ah receptor gene are not involved in lung cancer. Pharmacogenetics, 5, 151-8.
  31. Lai TJ, Tsai YY, Cheng YW, et al (2006). An association between BPDE-like DNA adduct levels and p53 gene mutation in pterygium. Mol Vis, 12, 1687-91.
  32. Lazarus P, Stern J, Zwiebel N, et al (1996). Relationship between p53 mutation incidence in oral cavity squamous cell carcinomas and patient tobacco use. Carcinogenesis, 17, 733-9
  33. Chen B, HuY, Jin T, et al (2007). The influence of metabolic gene polymorphis ms on urinary 1-hydroxypyrene concentration s in Chinese coke oven workers. Sci Total Environ, 381, 38-46.
  34. Cavalieri EL, Rogan EG (1995). Central role of radical cations in metabolic activation of polycyclic aromatic hydrocarbons. Xenobiotica, 25, 677-88.
  35. Celius T, Matthews J (2010). Functional analysis of six human aryl hydrocarbon receptor variants in human breast cancer and mouse hepatoma cell lines. Toxicology, 277, 59-65.
  36. Chen Y, Bai Y, Yuan J, et al (2006). Associationof polymorphisms in AhR, CYP1A1, GSTM1, and GSTT1 genes with levels of DNA damage in peripheral blood lymphocytes among coke-oven workers. Cancer Epidemiol Biomarkers Prev 15, 1703-07.
  37. Denissenko MF, Pao A, Tang M, et al (1996). Preferential formation of benzo (a) pyrene adducts at lung cancer mutational hotspots in P53. Science, 274, 430-2.
  38. Eaton DL, Bammler TK (1999). Concise review of the glutathione s-transferases and their significance to toxicology. Toxicol Sci, 49, 156-64.
  39. Gao M, Li Y, Sun YL, et al (2011). A common carcinogen benzo[a]pyrene causes p53 overexpression in mouse cervix via DNA damage. Mutat Res, 724, 69-75.
  40. Garritano S, Inga A, Gemignani F, et al (2013). More targets, more pathways and more clues for mutant p53. Oncogenesis, 2, 54.
  41. Giri SK, Yadav A, Kumar A, et al (2012). CYP1A1 gene polymorphisms: modulator of genetic damage in coal-tar workers. Asian Pac J Cancer Prev, 13, 3409-16.
  42. Gonzalez R, Silva JM, Sanchez A, et al (2000). Microsatellite alterations and TP53 mutations in plasma DNA of smallcell lung cancer patients: followup study and prognostic significance. Oncology, 11, 1097-104.
  43. Alexandrie AK, Warholm M, Carstensen U, et al (2000). CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure. Carcinogenesis, 21, 669-76.
  44. Bartsch H, Nair U, Risch A, et al (2000). Genetic polymorphism of CYP genes, alone or in combination as a risk modifier of tobacco related cancers. Cancer Epidemiol Biomark Prev, 9, 3-28.
  45. Baselt RC (1980). Biological monitoring methods for industrial chemicals. Davis, CA: Biomedical Publications, 207-11.
  46. Bin P, Leng S, Cheng J, et al (2008). Association of aryl hydrocarbon receptor gene polymorphisms and urinary 1-hydroxypyrene in polycyclic aromatic hydrocarbonexposed workers. Cancer Epidemiol Biomarkers Prev, 17, 1702-08.
  47. Board P, Coggan M, Johnston P, et al (1990). Genetic heterogeneity of the human glutathione transferases: a complex of gene families. Pharmacol Ther, 48, 357-69.
  48. Bufalo NE, Leite JL, Guilhen AC, et al (2006). Assumpcao and laura s ward. Smoking and susceptibility to thyroid cancer: an inverse association with CYP1A1 allelic variants. Endocr Relat Cancer, 13, 1185-93.
  49. Castano-Vinyals G, D'Errico A, Malats N, et al (2004). Biomarkers of exposure to polycyclic aromatic hydrocarbons from environmental air pollution. Occup Environ Med, 61,12.

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