Archives of Toxicology

, Volume 81, Issue 10, pp 711–718 | Cite as

Genotype and allele frequencies of polymorphic CYP2E1 in the Turkish population

Toxicokinetics and Metabolism


Cytochrome P4502E1 (CYP2E1) gene shows genetic polymorphisms that vary markedly in frequency among different ethnic and racial groups. We studied the genotype distributions and allele frequencies of three CYP2E1 polymorphisms: CYP2E1*5B (RsaI/PstI RFLP, C-1053T/G-1293C SNP, rs2031920 /rs3813867), CYP2E1*6 (DraI RFLP, T7632A SNP, rs6413432), and CYP2E1*7B (DdeI RFLP, G-71T SNP, rs6413420) by PCR/RFLP technique in a sample of 206 healthy subjects representing Turkish population. CYP2E1*5B polymorphism analysis yielded the genotype distribution as 96.12% for *1A/*1A (c1/c1), and 3.88% for *1A/*5B (c1/c2). The genotype frequencies for CYP2E1*6 polymorphism were found as 83.98% for *1A/*1A (T/T), 15.53% for *1A/*6 (T/A) and 0.49% for *6/*6 (A/A). For CYP2E1*7B (G-71T) polymorphism, the genotype frequencies were determined to be 86.89% for *1A/*1A (G/G), 12.62% for *1A/*7B (G/T) and 0.49% for *7B/*7B (T/T). Accordingly, the allele frequencies for *5B, *6 and *7B were 1.94, 8.25, and 6.80%, respectively. The genotype distributions of CYP2E1*5B and *6 in Turkish population were similar to those in other Caucasian populations, while differed significantly from East Asian populations. Recently, a novel and functionally important CYP2E1*7B polymorphism was identified in the promoter region. There have been few studies and limited data on CYP2E1*7B polymorphism frequency in the world and, so far, no information has been available for Turkish population. The genotype frequencies of CYP2E1*7B in Turkish population were found to be similar to those of other Caucasian populations. Population studies like this could be useful in assessing the susceptibility of different populations to chemical-induced diseases, including several types of cancer.


CYP2E1 gene Turkish population Genetic polymorphism Allele frequencies CYP2E1*5B, *6, *7B 


  1. Ada AO, Süzen SH, Iscan M (2004) Polymorphisms of cytochrome P450 1A1, gluthatione S-transferases M1 and T1 in a Turkish population. Toxicol Lett 151:311–315PubMedCrossRefGoogle Scholar
  2. Aktas D, Ozen H, Atsu N, Tekin A, Sozen S, Tuncbilek E (2001) Glutathione S-transferase M1 gene polymorphism in bladder cancer patients: a marker on invasive bladder cancer? Cancer Genet Cytogen 125:1–4CrossRefGoogle Scholar
  3. Arinç E, Adali O (1983) Solubilization and partial purification of 2 forms of cytochrome P-450 from trout liver microsomes. Comp Biochem Phys B 76:653–662CrossRefGoogle Scholar
  4. Arinç E, Adali O, Gencler-Ozkan AM (2000a) Induction of N-nitrosodimethylamine metabolism in liver and lung by in vivo pyridine treatments of rabbits. Arch Toxicol 74:329–334CrossRefGoogle Scholar
  5. Arinç E, Adali O, Gençler-Özkan AM (2000b) Stimulation of aniline, p-nitrophenol and N-nitrosodimethylamine metabolism in kidney by pyridine treatments of rabbits. Arch Toxicol 74:527–532CrossRefGoogle Scholar
  6. Arinç E, Arslan S, Adali O (2005) Differential effects of diabetes on CYP2E1 and CYP2B4 proteins and associated drug metabolizing enzyme activities in rabbit liver. Arch Toxicol 79(8):427–433PubMedCrossRefGoogle Scholar
  7. Arinç E, Arslan S, Bozcaarmutlu A, Adali O (2007) Effects of diabetes on rabbit kidney and lung CYP2E1 and CYP2B4 expression and drug metabolism and potentiation of carcinogenic activity of N-nitrosodimethylamine in kidney and lung. Food Chem Toxicol 45(1):107–118PubMedCrossRefGoogle Scholar
  8. Arinç E, Philpot RM (1976) Preparation and properties of partially purified pulmonary cytochrome P-450 from rabbits. J Biol Chem 25:3213–3220Google Scholar
  9. Aynacioglu AS, Brockmoller J, Bauer S, Sachse C, Guzelbey P, Ongen Z, Nacak M, Roots I (1999) Frequency of cytochrome P4502C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48:409–415PubMedCrossRefGoogle Scholar
  10. Balta G, Yuksek N, Ozyurek E, Ertem U, Hicsonmez G, Altay C, Gurgey A (2003) Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 Genotypes in Childhood Acute Lymphoblastic Leukemia. Am J Hematol 71:154–160CrossRefGoogle Scholar
  11. Bolt HM, Roos PH, Thier R (2003) The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals: consequences for occupational and environmental medicine. Int Arch Occup Environ Health 76:174–185PubMedGoogle Scholar
  12. Bouchardy C, Hirvonen A, Coutelle C, Ward PJ, Dayer P, Benhamou S (2000) Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract. Int J Cancer 87:734–740PubMedCrossRefGoogle Scholar
  13. Brockmöller J, Cascorbi I, Kerb R, Roots I (1996) Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk. Cancer Res 56(17):3915–3925PubMedGoogle Scholar
  14. El-Zein R, Zwischenbergher JB, Wood TG, Abdel Rahman SZ, Brekelbaum C, Au WW (1997) Combined genetic polymorphism and risk for development of lung cancer. Mutat Res 381:189–200PubMedGoogle Scholar
  15. Ernstgard L, Warholm M, Johanson G. (2004) Robustness of chlorzoxazone as an in vivo measure of cytochrome P450 2E1 activity. Br J Clin Pharmacol 58(2):190–200PubMedCrossRefGoogle Scholar
  16. Fairbrother A, Grove J, de Waziers I, Steimel DT, Day CD, Crespi CL, Daly AK (1998) Detection and characterization of novel polymorphisms in the CYP2E1 gene. Pharmacogenetics 8:543–552PubMedCrossRefGoogle Scholar
  17. Farker K, Lehmann MH, Oelschlagel B, Haerting J, Hoffmann A, Janitzky V, Schubert J (1998) Impact of CYP2E1 genotype in renal cell and urothelial cancer patients. Exp Toxicol Pathol 50:425–431PubMedGoogle Scholar
  18. Garte S, Gaspari L, Alexandrie A-K, Ambrosone C, Autrup H, Autrup JI, Baranova H, Bathum L, Benhamou S, Boffetta P, Bouchardy C, Breskvar K, Brockmöller J, Cascorbi I, Clapper ML, Coutelle C, Daly A, Dell’Omo M, Dolzana V, Dresler CM, Fryer A, Haugen A, Hein DW, Hildesheim A, Hirvonen A, Hsich L-L, Ingelman-Sundberg M, Kalina I, Kang D, Kihara M, Kiyohara C, Kremers P, Lazarus P, Le Marchand L, Lechner MC, Lieshout EMM, London S, Manni JJ, Maugard CM, Morita S, Nazar-Stewart V, Noda K, Oda Y, Parl FF, Pastorelli R, Persson I, Peters WHM, Rannug A, Rebbeck T, Risch A, Roelandt L, Romkes M, Ryberg D, Salagovic J, Schoket B, Seidegard J, Shileds PG, Sim E, Sinhet D, Strange RC, Stücker I, Sugimura H, To-Figueras J, Vineis P, Yu MC, Taioli E (2001) Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol. Biomarkers Prev 10:1239–1248PubMedGoogle Scholar
  19. Guengerich FP, Kim DH, Iwasaki M (1991) Role of human cytochrome P450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 4:168–179PubMedCrossRefGoogle Scholar
  20. Haufroid V, Buchet JP, Gardinal S, Lison D (2002) Cytochrome P4502E1 phenotyping and the measurement of the chlorzoxazone metabolic ratio: assessment of its usefulness in workers exposed to styrene. Int Arch Occup Environ Health 75:453–458PubMedCrossRefGoogle Scholar
  21. Hayashi S, Watanabe J, Kawajiri K (1991) Genetic polymorphisms in the 5′-flanking region change transcriptional regulation of the human cytochrome P450IIEI gene. J Biochem 110:559–565PubMedGoogle Scholar
  22. Hong J-Y, Pan J, Gonzales FJ, Gelboin HV, Yang CS (1987) The induction of a specific form of cytochrome P-450 (P-450j) by fasting. Biochem Biophys Res Commun 142:1077–1083PubMedCrossRefGoogle Scholar
  23. Ingelman-Sundberg M, Johansson I, Yin H, Terelius Y, Eliason E, Clot P, Albano E (1993) Ethanol-inducible cytochrome P4502E1: Genetic polymorphism, regulation, and possible role in the etiology of alcohol-induced liver disease. Alcohol 10:447–452PubMedCrossRefGoogle Scholar
  24. Johansson I, Ingelman-Sundberg M (1988) Benzene metabolism by ethanol-, acetone-, and benzene-inducible cytochrome P-450 (IIE1) in rat and rabbit liver microsomes. Cancer Res 48(19):5387–5390PubMedGoogle Scholar
  25. Kato S, Shields PG, Caporaso NE, Hoover RN, Trump BF, Sugimura H, Weston A, Harris CC (1992) Cytochrome P4502E1 genetic polymorphisms, racial variation, and lung cancer risk. Cancer Res 52:6712–6715PubMedGoogle Scholar
  26. Kharasch ED, Thummel KE (1993) Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiol 79:795–807CrossRefGoogle Scholar
  27. Konishi T, Calvillo M, Leng A-S, Feng J, Lee T, Lee H, Smith JL, Sial SH, Berman N, French S, Eysselein V, Lin K-M, Wan Y-JY (2003) The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men. Exp Mol Pathol 74:183–189PubMedCrossRefGoogle Scholar
  28. Koop DR, Casazza JP (1985) Identification of ethanol-inducible P-450 isozyme 3a as the acetone and acetol monooxygenase of rabbit microsomes. J Biol Chem 260:13607–13612PubMedGoogle Scholar
  29. Lieber CS (1997) Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev 77(2):517–543PubMedGoogle Scholar
  30. Liu S, Park JY, Schantz SP, Stern JC, Lazarus P (2001) Elucidation of CYP2E1 5′ regulatory RsaI/PstI allelic variants and their role in risk for oral cancer. Oral Oncol 37:437–445PubMedCrossRefGoogle Scholar
  31. Lu AYH, Levin W (1974) The resolution and reconstitution of the liver microsomal hydroxylation system. Biochem Biophys Acta 344:205–240PubMedGoogle Scholar
  32. Neuhaus T, Ko Y-D, Lorenzen K, Fronhoffs S, Harth V, Bröde P, Vetter H, Bolt HM, Pesch B, Brüning T (2004) Association of cytochrome P450 2E1 Polymorphisms and head and neck squamous cell cancer. Toxicol Lett 151:273–282PubMedCrossRefGoogle Scholar
  33. Nishimoto IN, Hanaoka T, Sugimura H, Nagura K, Ihara M, Li X-J, Arai T, Hamada GS, Kowalski LB, Tsugane S (2000) Cytochrome P450 2E1 polymorphism in gastric cancer in Brazil: cas-control studies of Japanese Brazilians and non-Japanese Brazilians. Cancer Epidem Biomark Prev 9:675–680Google Scholar
  34. Omer B, Ozbek U, Akkose A, Kilic G (2001) Genetic polymorphism of cytochrome P450 2E1 in the Turkish population. Cell Biochem Funct 19:273–275PubMedCrossRefGoogle Scholar
  35. Oyama T, Kawamato T, Mizoue T, Sugio K, Kodama Y, Mitsudomi T, Yasumoto K (1997) Cytochrome P4502E1 polymorphism as a risk factor for lung cancer: in relation to p53 gene mutation. Anticancer Res 17:583–588PubMedGoogle Scholar
  36. Persson I, Johansson I, Lou YC, Yue QY, Duan LS, Bertilsson L, Ingelman-Sundberg M (1999) Genetic polymorphism of xenobiotic metabolizing enzymes among Chinese kung cancer patients. Int J Cancer 81:325–329PubMedCrossRefGoogle Scholar
  37. Peter H, Deutschmann S, Reichel C, Hallier E (1989) Metabolism of methyl chloride by human erythrocytes. Arch Toxicol 72:454–455Google Scholar
  38. Peter R, Böker R, Beaune PH, Iwasaki M, Guengerich FP, Yang CS (1990) Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P-450IIEI. Chem Res Toxicol 3:566–573PubMedCrossRefGoogle Scholar
  39. Pinarbasi H, Silig Y, Seyfikli Z, Celik VK, Pinarbasi E (2001) Genetic polymorphism of GSTM1 in Turkish lung cancer patients. Toxicol Lett 123(Suppl 1):115Google Scholar
  40. Quinones L, Lucas D, Godoy J, Caceres D, Berthou F, Varela N, Lee K, Acevedo C, Martinez L, Aguilera AM, Gil L (2001) CYP1A1, CYP2E1 and GSTM1 genetic polymorphisms. The effect of single and combined genotypes on lung cancer susceptibility in Chilean people. Cancer Lett 174:35–44PubMedCrossRefGoogle Scholar
  41. Sikdar N, Mahmud ASk, Paul RR, Roy B (2003) Polymorphism in CYP1A1 and CYP2E1 genes and susceptibility to leukoplakia in Indian tobacco users. Cancer Lett 195(1):33–42PubMedCrossRefGoogle Scholar
  42. Song BJ, Matsunaga T, Hardwick JP, Park SS, Veech RL, Yang CS, Gelboin HV, Gonzales FJ (1987) Stabilization of cytochrome P450j messenger ribonucleic acid in the rat. Mol Endocrinol 1:542–547PubMedCrossRefGoogle Scholar
  43. Thier R, Lewalter J, Selinski S, Bolt HM (2002) Possible impact of human CYP2E1 polymorphisms on the metabolism of acrylonitrile. Toxicol Lett 128:249–255PubMedCrossRefGoogle Scholar
  44. Uematsu F, Ikawa S, Kikuchi H, Sagami I, Kanamaru R, Abe T, Satoh K, Motomiya M, Watanabe M (1994) Restriction fragment length polymorphism of the human CYP2E1 (cytochrome P450IIE1) gene and susceptibility to lung cancer: possible relevance to low smoking exposure. Pharmacogenet 4(2):58–63Google Scholar
  45. Uematsu F, Kikuchi H, Motomiya M, Abe T, Sagami I, Ohmachi T, Wakui A (1991) Association between restriction fragment length polymorphism of the human cytochrome P450 2E1 gene and susceptibility to lung cancer. Jpn J Cancer Res 82:254–256PubMedGoogle Scholar
  46. Umeno M, McBridge OW, Yang CS, Gelboin HV, Gonzales FJ (1988) Human ethanol-inducible P450IIEI: complete gene sequence, promoter characterization, chromosome mapping and cDNA-directed expression. Biochemistry 27:9006–9013PubMedCrossRefGoogle Scholar
  47. Vodicka P, Soucek P, Tates AD, Dusinska M, Sarmanova J, Zamecnikova M, Vodickova L, Koskinen M, Zwart FA, Natajaran AT, Hemminki K (2001) Association between genetic polymorphisms and biomarkers in styrene-exposed workers. Mutat Res 482:89–103PubMedGoogle Scholar
  48. Wang S-L, Lee H, Chen K-W, Tsai K-J, Chen C-Y, Lin P (1999) Cytochrome P4502E1 genetic polymorphisms and lung cancer in a Taiwanese population. Lung Cancer 26:27–34PubMedCrossRefGoogle Scholar
  49. Watanabe J, Hayashi S, Nakachi K, Imai K, Suda Y, Sekine T, Kawajiri K (1990) PstI and RsaI RFLPs in complete linkage disequilibrium at the CYP2E gene. Nucleic Acids Res 18(23):7194PubMedCrossRefGoogle Scholar
  50. Wu X, Amos CI, Kemp BL, Shi H, Jiang H, Wan Y, Spitz MR (1998) Cytochrome P450 2E1 DraI polymorphism in lung cancer in minority populations. Cancer Epidemiol Biomark Prev 7:13–18Google Scholar
  51. Wu X, Shi H, Jiang H, Kemp B, Hong WK, Delclos GL, Spitz MR (1997) Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer. Carcinogenesis 18(5):967–73PubMedCrossRefGoogle Scholar
  52. Yang B-M, O’Reilly DA, Demaine AG, Kingsnorth AN (2001) Study of polymorphisms in the CYP2E1 gene in patients with alcoholic pancreatitis. Alcohol 23:91–97PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Biochemistry Graduate Programme and Department of Biological SciencesMiddle East Technical UniversityAnkaraTurkey

Personalised recommendations