Cytochrome P450 1A1, 2E1 and GSTM1 Gene Polymorphisms and Susceptibility to Colorectal Cancer in the Saudi Population

  • Saeed, Hesham Mahmoud (Department of Biochemistry, College of Science, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Alanazi, Mohammad Saud (Department of Biochemistry, College of Science, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Nounou, Howaida Attia (Department of Medical Biochemistry, Faculty of Medicine, Alexandria University) ;
  • Shalaby, Manal Ali (Genetic Engineering and Biotechnology Research Institute (GEBRI), City for Scientific Research and Technology Applications) ;
  • Semlali, Abdelhabib (Department of Biochemistry, College of Science, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Azzam, Nahla (Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Aljebreen, Abdeulrahan (Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Alharby, Othman (Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Parine, Narasimha Reddy (Department of Biochemistry, College of Science, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Shaik, Jilani (Department of Biochemistry, College of Science, Faculty of Medicine, King Khalid University Hospital, King Saud University) ;
  • Maha, Maha
  • Published : 2013.06.30


Background: The Saudi population has experienced a sharp increase in colorectal and gastric cancer incidences within the last few years. The relationship between gene polymorphisms of xenobiotic metabolizing enzymes and colorectal cancer (CRC) incidence has not previously investigated among the Saudi population. The aim of the present study was to investigate contributions of CYP1A1, CYP2E1, and GSTM1 gene polymorphisms. Materials and Methods: Blood samples were collected from CRC patients and healthy controls and genotypes were determined by polymerase chain reaction restriction fragment length polymorphism and sequencing. Results and Conclusions: $CYP2E1^*6$ was not significantly associated with CRC development (odd ratio=1.29; confidence interval 0.68-2.45). A remarkable and statistically significant association was observed among patients with $CYP1Awt/^*2A$ (odd ratio=3.65; 95% confidence interval 1.39-9.57). The $GSTM1^*0/^*0$ genotype was found in 2% of CRC patients under investigation. The levels of CYP1A1, CYP2E1 and GSTM1 mRNA gene expression were found to be 4, 4.2 and 4.8 fold, respectively, by quantitative real time PCR. The results of the present case-control study show that the studied Saudi population resembles Caucasians with respect to the considered polymorphisms. Investigation of genetic risk factors and susceptibility gene polymorphisms in our Saudi population should be helpful for better understanding of CRC etiology.


  1. Ates NA, Tamer L, Ates C, et al (2005). Glutathione S-transferase M1, T1, P1 genotypes and risk for development of colorectal cancer. Biochem Genet, 43, 149-63.
  2. Bell DA, Taylor JA, Paulson DF, et al (1993). Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen metabolism gene glutathione S-transferase M1(GSTM1) that increases susceptibility to bladder cancer. J Natl Cancer Inst, 85, 1159-64.
  3. Boccia S, Sayed-Tabatabaei FA, Persiani R, et al (2007). Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population. BMC Cancer, 7, 206.
  4. Boyle P, Ferlay J (2005). Cancer incidence and mortality in Europe. Ann Oncol, 16, 481-8.
  5. Bozina N, Bradamanye V, Loveric M (2009). Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity and cancer risk. Arch Hig Rada Toksikol, 60, 217-42.
  6. Brookes AJ (1999). The essence of SNPs. Gene, 234, 177-86.
  7. Carlson CS, Newman TL, Nickerson DA (2001). SNPing in the human genome. Curr Opin Chem Biol, 5, 78-85.
  8. Chang BL, Zheng SL, Isaacs SD, et al (2003). Polymorphisms in the CYP1A1 gene are associated with prostate cancer risk. Int J Cancer, 106, 375-8.
  9. Chang HY, Yang X (2000). Proteases for cell suicide: functions and regulation of caspases. Microbiol Mol Biol Rev, 64, 821-46.
  10. Corchero J, Primprale S, Kimura S, et al (2001) Organization of the CYP1A cluster on human chromosome 15: implications for gene regulation. Pharmacogenetics, 11, 1-6.
  11. Darazy M, Balbaa M, Mugharbil A, et al (2011). CYP1A1, CYP2E1, and GSTM1 Gene Polymorphisms and Susceptibility to Colorectal and Gastric Cancer Among Lebanese. Genet Test Mol Biomarkers, 15, 423-9.
  12. Dil Llio C, Del Boccio G, Casaccia R, et al (1987). Selenium level and glutathione dependent enzyme activities in normal and neoplastic human lung tissues. Carcinogenesis, 8, 281-4.
  13. Gao Y, Cao Y, Tan A, et al (2010). Glutathione S-transferase M1 polymorphisms and sporadic colorectal cancer risk: an updating meta analysis and HuGE review of 36 case-control studies. Ann Epidemiol, 20, 108-21.
  14. Garte S, Gaspari L, Alexandrie AK, et al (2001). Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev, 10, 1239-48.
  15. Gelboin H (1980). Benzo[a]pyrene metabolism, activation and carcinogenesis: role of regulation of mixed-function oxidases and related enzymes. Physio Rev, 60, 1107-66.
  16. Guengerich FP, Shimada T (1998). Activation of procarcinogens by human cytochrome P450 enzymes. Mutat Res, 400, 201-13.
  17. Haufroid V, Buchet JP, Gardinal S, et al (2002). Cytochrome P450 2E1 phenotyping by the measurement of the chloroxazone metabolic ratio: assessment of its usefulness in workers exposed to styrene. Int Arch Occup Environ Health, 75, 453-8.
  18. Hayashi S, Watanabe J, Nakachi K, et al (1991). Genetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450 1A1 gene. J Biochem (Tokyo), 110, 407-11.
  19. Hayashi S, Watanabe J, Kawajiri K (1991). Genetic polymorphisms in the 5’-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J Biochem, 110, 559-65.
  20. Heavey PM, McKenna D, Rowland IR (2004). Colorectal cancer and relationship between genes and the environment. Nutr Cancer, 48, 124-41.
  21. Hemminki K, Czene K (2002). Attributable risks of familial cancer from the family-cancer database. Cancer Epidemiol Biomarkers Prev, 12, 1638-44.
  22. Induski JA, Lutz W (2000). Metabolic genotype in relation to individual susceptibility to environmental carcinogens. Int Arch Occup Environ Health, 73, 71-85.
  23. Katoh T, Nagata N, Kuroda Y, et al (1996). Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. Carcinogenesis, 17, 1855-9.
  24. Kellerman G, Shaw CR, Luyten-Kellerman M (1973). Arylhydrocarbon hydroxylase and bronchogenic carcinoma. N Engl J Med, 289, 934-7.
  25. Ketterer B, Harris JM, Talaska G, et al (1992). The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer. Environ Health Perspect, 98, 87-94.
  26. Kiss I, Ne´meth A, Bogner B, et al (2004) Polymorphisms of glutathione-S-transferase and arylamine N- acetyltransferase enzymes and susceptibility to colorectal cancer. Anticancer Res, 24, 3965-70.
  27. Landi MT, Bertazzi PA, Shields PG, et al (1994). Association between CYP1A1 genotype, mRNA expression and enzymatic activity in humans. Pharmacogenetics, 4, 242-6.
  28. Lionel L, Abdelhabib S, Marc B, et al (2010). Crosstalk between T cells and bronchial fibroblasts obtained from asthmatic subjects involves CD40L/α5β1 interaction. Mol Immunol, 47, 2112-8.
  29. Liu Y, Meng XW, Zhou LY, et al (2009). Genetic polymorphism and mRNA levels of cytochrome P450IIE1 and glutathione S-transferase P1 in patients with alcoholic liver disease in different nationalities. Hepatobiliary Pancreat Dis Int, 8, 162-7.
  30. Lucas D, Menez C, Girre C, et al (1995). Cytochrome P450 2E1 genotype and chlorzoxazone metabolism in healthy and alcoholic Caucasian subjects. Pharmacogenetics, 5, 298-304.
  31. Martınez C, Martın F, Fernandez JM, et al (2006). Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans. Pharmacogenomics, 7, 711-8.
  32. Nisa H, Kono S, Yin G, et al (2010). Cigarette smoking, genetic polymorphisms and colorectal cancer risk: the Fukuoka colorectal cancer study. BMC Cancer, 10, 274.
  33. Parkin DM, Bray F, Ferlay J, et al (2005). Global cancer statistics 2002. CA Cancer J Clin, 55, 74-108.
  34. Piao JM, Shin MH, Kweon SS, et al (2009). Glutathione-Stransferase (GSTM1, GSTT1) and the risk of gastrointestinal cancer in a Korean population. World J Gastroenterol, 15, 5716-21.
  35. Potter JD (1999). Colorectal cancer: molecules and populations. J Natl Cancer Inst, 91, 916-32.
  36. Rawal RM, Patel DD, Patel BP, et al (1999). Assessment of glutathione S-transferase and glutathione reductase in patients with squamous cell carcinoma of buccal musosa. Int J Cancer, 83, 727-31.<727::AID-IJC5>3.0.CO;2-P
  37. Raunio H, Husgafvel-Pursiainen K, Anttila S, et al (1995). Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility. Gene, 159, 113-21.
  38. Roses AD (2000). Pharmacogenetics and the practice of medicine. Nature, 405, 857-65.
  39. Sachidanandam R, Weissman D, Schmidt SC, et al (2001). A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature, 409, 928-33.
  40. Saadat I, Saadat M (2001). Glutathione S-transferase M1 and T1 null genotypes and the risk of gastric and colorectal cancers. Cancer Lett, 169, 21-6.
  41. Sanger F, Nicklen S, Coulson A (1977). DNA sequencing with chain terminating inhibitor. Proc Natl Acad Sci (USA), 74, 5463-7.
  42. Sgambato A, Campisi B, Zupa A, et al (2002). Glutathione S-transferase (GST) polymorphisms as risk factors for cancer in a highly homogeneous population from southern Italy. Anticancer Res, 22, 3647-52.
  43. Slattery ML, Samowtiz W, Ma K, et al (2004). CYP1A1, cigarette smoking, and colon and rectal cancer. Am J Epidemiol, 160, 842-52.
  44. Sivarman L, Leatham MP, Yee J (1994). CYP1A1 genetic polymorphisms and in situ colorectal cancer. Cancer Res, 54, 3692-5.
  45. Tamer L, Ates NA, Ates C, et al (2005). Glutathione S-transferase M1, T1 and P1 genetic polymorphisms, cigarette smoking and gastric cancer risk. Cell Biochem Funct, 23, 267-72.
  46. Taspinar M, Ayodos SE, Comez O, et al (2008). CYP1A1, GST gene polymorphisms and risk of chronic myeloid leukaemia. Swiss Med Wkly, 138, 12-7.
  47. Terry KL, Garner EO, Vitonis AF, et al (2003). Interaction between CYP1A1 polymorphic variants and dietary exposures influencing ovarian cancer risk. Cancer Epidemiol Biomarkers Prev, 12, 187-90.
  48. Wang H, Zhou Y, Zhuang W, et al (2010). Glutathione Stransferase M1 null genotype associatedwith gastric cancer among Asians. Dig Dis Sci, 55, 1824-30.
  49. Welfare M, Monesola Adeokun A, Bassendine MF, et al (1999). Polymorphism in GSTP1, GSTM1, and susceptibility to colorectal cancer. Cancer Epidemiol Biomarkers Prev, 8, 289-92.
  50. Wenlei Z, Liang Z, Zhinqun Q, et al (2012). Does cytochrome P450 1A1 MspI polymorphism increase acute lymphoblastic leukemia risk? Evidence from 2013 cases and 2903 controls. Gene, 510, 14-21.
  51. Wu MS, Chen CJ, Lin MT, et al (2002). Genetic polymorphisms of cytochrome P450 2E1, glutathione S-transferase M1 and T1, and susceptibility to gastric carcinoma in Taiwan. Int J Colorectal Dis, 17, 338-43.
  52. Ye Z, Parry JM (2002). Genetic polymorphisms in the cytochrome P450 1A1, glutathione S- transferase M1 and T1, and susceptibility to colon cancer. Teratog Carcinog Mutagen, 22, 385-92.
  53. Zhou SF, Liu JP, Chowbay B (2009) Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev, 41, 89-295.

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