Pathology & Oncology Research

, Volume 18, Issue 3, pp 651–656 | Cite as

Association of GSTM1, GSTT1, GSTP1 and CYP2E1 Single Nucleotide Polymorphisms with Colorectal Cancer in Iran

  • Saeideh Ebrahimkhani
  • Ali Mohammad Asgharian
  • Babak Nourinaier
  • Khadijeh Ebrahimkhani
  • Nasrin Vali
  • Fatemeh Abbasi
  • Mohammad Reza Zali


Colorectal cancer is a major cause of morbidity and mortality both globally and in Iran. The aim of this study was to determine the association between genetic polymorphisms of glutathione S-transferases P1, M1 and T1 (GSTP1, M1, T1) and susceptibility to colorectal cancer (CRC). Genotyping of GSTP1, GSTM1 and GSTT1 was performed by the use of pyrosequencing. One hundred cases and healthy controls were enrolled into this study. Mean GSTT1 polymorphism type was significantly (P < 0.01) higher in cases as compared to controls (P < 0.0001: OR, 2.43: 95% CI, 1.47-4). On the other hand there is no significant association between GSTM1, GSTP1 and colorectal cancer. GSTs measurement may be useful as a colorectal marker in colorectal cancer and biopsies obtained at colonoscopy can be used to measure tumor markers.


Glutathione S-transferases Colorectal cancer Cytochrome P4502E1 Iran 



We thank all members of Lab at Research Center for Gastroenterology and Liver Disease for their helpful comments and constructive discussions on this project and providing grant support as well.


  1. 1.
    Guengerich FP (1992) Metabolic activation of carcinogens. Pharmacol Ther 54:17–61PubMedCrossRefGoogle Scholar
  2. 2.
    Guengerich FP, Shimada T (1991) Oxidation of toxic and carcinogenic chemicals by human cytochrome P- 450 enzymes. Chem Res Toxicol 4:391–407PubMedCrossRefGoogle Scholar
  3. 3.
    Doll R, Peto R (1981) The causes of cancers: quantitative estimates of avoidable risks of cancers in the United States today. J Natl Cancer Inst 66(6):1191–1308PubMedGoogle Scholar
  4. 4.
    Chasseaud LF (1979) The role of glutathione and glutathione S_transferases in the metabolism of chemical carcinogens and other electrophiles agents. Adv Cancer Res 29:175–274PubMedCrossRefGoogle Scholar
  5. 5.
    Coles B, Ketterer B (1990) The role of glutathione transferases in chemical carcinogenesis. Crit Rev Biochem MolBiol 25:47–70CrossRefGoogle Scholar
  6. 6.
    Mucci LA, Wedren S, Tamimi RM, Trichopoulos D, Adami HO (2001) The role of gene-environment interaction in the aetiology of human cancer: examples from cancers of the large bowel, lung and breast. J Intern Med 249:477–493PubMedCrossRefGoogle Scholar
  7. 7.
    Kihara M, Kihara M, Noda K (1995) Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorphisms in a Japanese population. Carcinogenesis 16:2331–2336PubMedCrossRefGoogle Scholar
  8. 8.
    Lin DX, Tang YM, Peng Q, Lu SH, Ambrosone CB, Kadlubar FF (1998) Susceptibility to esophageal cancer and genetic polymorphisms in glutathione s- transferases T1, P1, and M1 and cytochrome P450 2E1. Cancer Epidemiology, Biomarker & Prey 7:1013–1018Google Scholar
  9. 9.
    Nebert DW, McKinnon RA, Puga A (1996) Human drug- metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol 15:273–280PubMedCrossRefGoogle Scholar
  10. 10.
    Cheng KK, Day NE, Duffy SW, Lam TH, Fok M, Wong J (1992) Pickled vegetables in the aetiology of esophageal cancer in Hong Kong Chinese. Lancet 339:1314–1318PubMedCrossRefGoogle Scholar
  11. 11.
    Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11(6):559–603PubMedCrossRefGoogle Scholar
  12. 12.
    Guengerich FP, Kim DH, Iwasaki M (1991) Role of human cytochrome P-450IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 4:168–179PubMedCrossRefGoogle Scholar
  13. 13.
    Gunter MJ, Watson MA, Loktionov AS et al (2005) No association between cytochrome P450 and glutathione S-transferase gene polymorphisms and risk of colorectal adenoma: results from the UK flexible sigmoidoscopy screening trial. Canc Epidemiol Biomarkers Prev 14(4):1028–30CrossRefGoogle Scholar
  14. 14.
    Nakajima T, Wang R-S, Nimura Y et al (1996) Expression of cytochrome P450s and glutathione S- transferases in human esophagus with squamous- cell carcinomas. Carcinogenesis 17:1477–1481PubMedCrossRefGoogle Scholar
  15. 15.
    Boyer TD, Kenney WC (1985) Preparation, characterization and properties of glutathione S-transferases. In: Zakim D, Vessey D (eds) Biochemical pharmacology and toxicology. Wiley, New YorkGoogle Scholar
  16. 16.
    Mannervik B, Awasthi YC, Board PG et al (1992) Nomenclature for human glutathione S-transferases. Biochem J 282:305–306PubMedGoogle Scholar
  17. 17.
    Meyer DJ, Coles B, Pemble SE, Gilmore KS, Fraser GM, Ketterer B (1991) θ, a new class of glutathione transferases purified from rat and man. Biochem J 274:409–414PubMedGoogle Scholar
  18. 18.
    Lin D, Meyer DJ, Ketterer B, Lang NP, Kadlubar FF (1994) Effects of human and rat glutathione S-transferases on the covalent bonding of the N-acetoxy derivatives of heterocyclic amine carcinogens in vitro: a possible mechanism of organ specificity in their carcinogenesis. Cancer Res 54:4920–4926PubMedGoogle Scholar
  19. 19.
    Pemble S, Schroeder KR, Spenser SR et al (1994) Human glutathione S-transferase (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 300:271–276PubMedGoogle Scholar
  20. 20.
    Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–91PubMedCrossRefGoogle Scholar
  21. 21.
    Rebbeck TR (1997) Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomark Prev 6:733–743Google Scholar
  22. 22.
    Strange RC, Lear JT, Fryer AA (1998) Glutathione S-transferase polymorphisms: influence on susceptibility to cancer. Chem Biol Interact 24(111–112):351–364CrossRefGoogle Scholar
  23. 23.
    Nomania H, Mohammadzadeh Ghobadloob S, Yaghmaeib B, Rezvaniea NA, Yaghmaeic K (2005) Glutathione S-transferases activity in patients with colorectal cancer. Clin Biochem 38:621–624CrossRefGoogle Scholar
  24. 24.
    Rajagopal R, Deakin M, Fawole AS et al (2005) Glutathione S- transferase T1 polymorphisms are associated with outcome in colorectal cancer. Carcinogenesis 26(12):2157–2163PubMedCrossRefGoogle Scholar
  25. 25.
    Srivastava SK, Singhal SS, Hu X, Awasthi YC, Zimniak P, Singh SV (1999) Differential catalytic efficiency of allelic variants of human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys 366:89–94PubMedCrossRefGoogle Scholar
  26. 26.
    Houlston RS (1999) Glutathione S-transferase M1 status and lung cancer risk: a meta-analysis. Cancer Epidemiol Biomark Prev 8:675–682Google Scholar
  27. 27.
    Baily R, Roodi N, Verrier CS, Yee CJ, Dupont WD, Parl F (1998) Breast cancer and CYP1A1, GSTM1, and GSTT1 polymorphisms: evidence of a lack of association in Caucasians and African Americans. Cancer Res 58:65–70Google Scholar
  28. 28.
    Saadat I, Saadat M (2001) Glutathione S-transferase M1 and T1 null genotypes and the risk of gastric and colorectal cancers. Cancer Letters 169:21–26PubMedCrossRefGoogle Scholar
  29. 29.
    de Jong M, Nolte IM, te Meerman GJ et al (2002) Low-penetrance genes and their involvement in colorectal cancer susceptibility. Cancer Epidemiol Biomarkers Prev 11:1332–52PubMedGoogle Scholar
  30. 30.
    Board PG (1981) Gene deletion and partial deficiency of the glutathione S-transferase (ligandin) system in man. FEBS Lett 135:12–14PubMedCrossRefGoogle Scholar
  31. 31.
    Pemble S, Schroeder KR, Spencer SS, Meyer DJ, Hallier E, Bolt HM (1994) Human glutathione S-transferase (GSTT1): cDNA cloning and the characterisation of a genetic polymorphism. Biochem J 300:271–276PubMedGoogle Scholar
  32. 32.
    Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J (1997) Molecular cloning, characterisation and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase π variants. Evidence for differential catalytic activity of the encoded proteins. J Biol Chem 272:10004–11112PubMedCrossRefGoogle Scholar
  33. 33.
    Casson AG, Zheng Z, Chiasson D et al (2003) Associations between genetic polymorphisms of Phase I and II metabolizing enzymes, p53 and susceptibility to esophageal adenocarcinoma. Cancer Detect Prev 27:139–146PubMedCrossRefGoogle Scholar
  34. 34.
    Tan W, Song N, Wang GQ et al (2000) Impact of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferases M1, T1, and P1 on susceptibility to esophageal cancer among high-risk individuals in China. Cancer Epidemiology Biomarkers Prev 9:551–556Google Scholar
  35. 35.
    Butler WJ, Ryan P, Roberts-Thomson IC (2001) Metabolic genotypes and risk for colorectal cancer. J Gastroenterology Hepatol 16:631–635CrossRefGoogle Scholar
  36. 36.
    Lu X M, Zang YM, Lin RY et al (2005) Relationship between genetic polymorphisms of metabolizing enzymes CYP2E1, GSTM1 and Kazakh’s esophageal squamous cell cancer in Xinjiang, China. World J Gastroenterol 28: 11(24): 3651-3654.Google Scholar
  37. 37.
    Xing D, Tan W, Song N, Lin D (2000) Genetic polymorphism in hOGG1and susceptibility to esophageal cancer in Chinese. Zhonghuayixue Yichuanxue Zazhi 17:377–380Google Scholar
  38. 38.
    Tan W, Chen GF, Xing DY, Song CY, Kadlubar FF, Lin DX (2001) Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population. Int J Cancer 95:96–101PubMedCrossRefGoogle Scholar
  39. 39.
    Tan W, Song N, Wang GQ et al (2000) Impact of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferases M1, T1, and P1 on susceptibility to esophageal cancer among high-risk individuals in China. Cancer Epidemiol Biomarkers Prev 9:551–556PubMedGoogle Scholar
  40. 40.
    Dong CH, Yu SZ, Chen GC, Zhao DM, Hu Y (1998) Association of polymorphisms of glutathioneS transferase M1 and T1 genotypes with elevated aflatoxin and increased risk of primary liver cancer. Shijie Huaren Xiaohua Zazhi 6:463–466Google Scholar
  41. 41.
    Thong S, Wyllie AH, Barnes D, Wolf CR, Spurr NK (1993) Relationship between the GSTMI genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis 14:1821–1824CrossRefGoogle Scholar
  42. 42.
    Chevenix-Trench G, Young J, Coggan M, Board P (1995) Glutathione S-transferase Ml, and Tl polymorphisms: susceptibility to colon cancer and age of onset. Carcinogenesis 16:1655–1657CrossRefGoogle Scholar
  43. 43.
    Katoh T, Nagata N, Kuroda Y et al (1996) Glutathione S-transferase MI (GSTM1), and Tl(GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis 17:1855–1859PubMedCrossRefGoogle Scholar
  44. 44.
    Deakin M, Elder J, Hendrickse C et al (1996) Glutathione S-transferase GSTI’l genotypes and susceptibility to cancer: studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers. Carcinogenesis 17:881–884PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2012

Authors and Affiliations

  • Saeideh Ebrahimkhani
    • 1
  • Ali Mohammad Asgharian
    • 2
  • Babak Nourinaier
    • 1
  • Khadijeh Ebrahimkhani
    • 4
  • Nasrin Vali
    • 1
  • Fatemeh Abbasi
    • 3
  • Mohammad Reza Zali
    • 1
  1. 1.Research Center for Gastroenterology and Liver DiseaseShahid Beheshti University of Medical SciencesTehranIran
  2. 2.Department of Cell and Molecular BiologyIslamic Azad University, Tonekabon BranchTonekabonIran
  3. 3.Department of Cell and Molecular BiologyAzarbaijan Tarbiat Molaem UniversityTonekabonIran
  4. 4.Zanjan University of Medical ScienceZanjanIran

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