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Licensed Unlicensed Requires Authentication Published by De Gruyter January 11, 2014

The pharmacogenetics of drug metabolizing enzymes in the Lebanese population

  • Safaa Ossaily and Nathalie K. Zgheib EMAIL logo

Abstract

Drug metabolizing enzymes (DMEs) play a major role in the metabolism and final elimination of most drugs and xenobiotics from the body. Both phase I and phase II enzymes are highly polymorphic. Most studies on the pharmacogenetics (PGx) of DMEs and its influence on interindividual variability have been conducted in Western countries. Middle Easterners, however, may have a different genetic makeup and may be exposed to different environmental factors when compared with their Western counterparts. Thus, results obtained in Western populations cannot be extrapolated to the population of the Middle East, and it is important to examine and document PGx differences and influences within the Middle Eastern population as there have been very little published data from this region. Herein, we provide an update on the genetic polymorphisms of DMEs that were studied in Lebanon and their impact on drug toxicity and efficacy. It is hoped that with more time, additional funds, and perseverance, the PGx of DMEs in Lebanon picks up and becomes closer in quantity and quality to that in the West.


Corresponding author: Nathalie K. Zgheib, MD, Faculty of Medicine, Department of Pharmacology and Toxicology, American University of Beirut, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon, Phone: 01/350000 Ext. 4846, E-mail:

Acknowledgments

Support was received from the AUB Medical Practice Plan (AUBMPP) and the Lebanese National Council for Scientific Research (LNCSR). We are grateful to Dr. Joseph Simaan for reviewing our manuscript.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

References

1. Tomalik-Scharte D, Lazar A, Fuhr A, Kirchheiner J. The clinical role of genetic polymorphisms in drug-metabolizing enzymes. Pharmacogenomics J 2008;8:4–15.10.1038/sj.tpj.6500462Search in Google Scholar PubMed

2. Mitri A, Esmerian MO, Simaan JA, Sabra R, Zghein NK. Pharmacogenetics and personalized medicine: the future for drug prescribing. J Med Liban 2010;58:101–4.Search in Google Scholar

3. Djaffar-Jureidini I, Chamseddine N, Keleshian S, Naoufal R, Zahed L, Hakime N. Pharmacogenetics of coumarin dosing: prevalence of CYP2C9 and VKORC1 polymorphisms in the Lebanese population. Genet Test Mol Biomark 2011;15:827–30.10.1089/gtmb.2010.0248Search in Google Scholar PubMed

4. Djaffar Jureidini I, Chamseddine N, Keleshian S, Naoufal R, Zahed L, Hakime N. Prevalence of CYP2C19 polymorphisms in the Lebanese population. Mol Biol Rep 2011;38:5449–52.10.1007/s11033-011-0700-ySearch in Google Scholar PubMed

5. Zgheib NK, Shamseddine AA, Geryess E, Tfayli A, Bazarbachi A, Salem Z, et al. Genetic polymorphisms of CYP2E1, GST, and NAT2 enzymes are not associated with risk of breast cancer in a sample of Lebanese women. Mutat Res 2013; 747–748:40–7.10.1016/j.mrfmmm.2013.04.004Search in Google Scholar PubMed

6. Issa S, Zgheib NK. The role of genetic polymorphisms of N-acetyltransferase 2 (NAT2) enzyme in the risk of bladder cancer in the Lebanese population [MS thesis]. Beirut, Lebanon: American University of Beirut, 2013.Search in Google Scholar

7. Dhaini HR, Levy GN. Arylamine N-acetyltransferase 1 (NAT1) genotypes in a Lebanese population. Pharmacogenetics 2000;10:79–83.10.1097/00008571-200002000-00010Search in Google Scholar PubMed

8. Yassine IA, Kobeissi L, Jabbour ME, Dhaini HR. N-Acetyltransferase 1 (NAT1) genotype: a risk factor for urinary bladder cancer in a Lebanese population. J Oncol 2012;2012:512976.10.1155/2012/512976Search in Google Scholar PubMed PubMed Central

9. Darazy M, Balbaa M, Mugharbil A, Saeed H, Sidani H, Abdel-Razzak Z. CYP1A1, CYP2E1, and GSTM1 gene polymorphisms and susceptibility to colorectal and gastric cancer among Lebanese. Genet Test Mol Biomark 2011;15:423–9.10.1089/gtmb.2010.0206Search in Google Scholar PubMed

10. Salem AH, Yaqoob A, Ali M, Handu S, Fadel R, Abu-Hijleh M, et al. Genetic polymorphism of the glutathione S-transferase M1 and T1 genes in three distinct Arab populations. Dis Markers 2011;31:311–6.10.1155/2011/796520Search in Google Scholar

11. Ellison CA, Abou El-Ella SS, Tawfik M, Lein PJ, Olson JR. Allele and genotype frequencies of CYP2B6 and CYP2C19 polymorphisms in Egyptian agricultural workers. J Toxicol Environ Health A 2012;75:232–41.10.1080/15287394.2012.641201Search in Google Scholar PubMed PubMed Central

12. Shahin MH, Khalifa SI, Gong Y, Hammad LN, Sallam MT, El Shafey M, et al. Genetic and non-genetic factors associated with warfarin dose requirements in Egyptian patient. Pharmacogenet Genom 2011;21:130–5.10.1097/FPC.0b013e3283436b86Search in Google Scholar PubMed PubMed Central

13. Ismail Hamdy S, Hiratsuka M, Narahara K, El-Enany M, Moursi N, Salah-Eldin Ahmed M, et al. Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population. Br J Clin Pharmacol 2002;53:596–603.10.1046/j.1365-2125.2002.01604.xSearch in Google Scholar PubMed PubMed Central

14. Amer MA, Ghattas MH, Abo-Elmatty DM, Abou-El-Ela SH. Evaluation of glutathione S-transferase P1 genetic variants affecting type-2 diabetes susceptibility and glycemic control. Arch Med Sci 2012;8:631–6.10.5114/aoms.2012.30286Search in Google Scholar PubMed PubMed Central

15. Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, et al. Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. Br J Clin Pharmacol 2003;55:560–9.10.1046/j.1365-2125.2003.01786.xSearch in Google Scholar PubMed PubMed Central

16. Hussein AG, Mohamed RH, Alghobashy AA. Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Cell Immunol 2012;279:42–5.10.1016/j.cellimm.2012.08.006Search in Google Scholar PubMed

17. Qumsieh R, Ali B, Abdulrazzaq Y, Osman O, Akawi N, Bastaki S. Identification of New alleles and the determination of alleles and genotypes frequencies at the CYP2D6 gene in emiratis. PLoS One 2011;6:e28943.10.1371/journal.pone.0028943Search in Google Scholar PubMed PubMed Central

18. Hussain K, Salah N, Hussain S, Hussain S. Investigate the role of glutathione S transferase (GST) polymorphism in development of hypertension in UAE population. Iran Red Crescent Med J 2012;14:479–82.Search in Google Scholar

19. Woolhouse NM, Qureshi MM, Bastaki SM, Patel M, Abdulrazzaq Y, Bayoumi RA. Polymorphic N-acetyltransferase (NAT2) genotyping of Emirates. Pharmacogenetics 1997;7: 73–82.10.1097/00008571-199702000-00010Search in Google Scholar PubMed

20. Jarrar YB, Ismail S, Irshaid YM. N-Acetyltransferase-2 (NAT2) genotype frequency among Jordanian volunteers. Int J Clin Pharmacol Ther 2010;48:688–94.10.5414/CPP48688Search in Google Scholar PubMed

21. Yousef AM, Bulatova N, Newman W, Hakooz N, Ismail S, Qusa H, et al. Allele and genotype frequencies of the polymorphic cytochrome P450 genes (CYP1A1, CYP3A4, CYP3A5, CYP2C9 and CYP2C19) in the Jordanian population. Mol Biol Rep 2012;39:9423–33.10.1007/s11033-012-1807-5Search in Google Scholar PubMed

22. Zihlif M, Imraish A, Irshaid YM. Frequency of certain single-nucleotide polymorphisms and duplication of CYP2D6 in the Jordanian population. Genet Test Mol Biomark 2012;16:1201–5.10.1089/gtmb.2012.0122Search in Google Scholar PubMed

23. Khabaz MN. The GSTP1 Ile105Val polymorphism is not associated with susceptibility to colorectal cancer. Asian Pac J Cancer Prev 2012;13:2949–53.10.7314/APJCP.2012.13.6.2949Search in Google Scholar

24. Naffa RG, Awidi AS, Yousef AM, Ismail SI. CYP1AI, glutathione S-transferase gene polymorphisms and risk of Polycythemia vera. Cancer Epidemiol 2012;36:68–72.10.1016/j.canep.2011.05.001Search in Google Scholar

25. Torkaman-Boutorabi A, Hoormand M, Naghdi N, Bakhshayes M, Milanian I. Genotype and allele frequencies N-Acetyl transferase 2 and glutathione S-transferase in the Iranian population. Clin Exp Pharmacol Physiol 2007;34:1207–11.10.1111/j.1440-1681.2007.04753.xSearch in Google Scholar

26. Azarpira N, Namazi S, Hendijani F, Banan M, Darai M. Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran. Pharmacol Rep 2010;62:740–6.10.1016/S1734-1140(10)70332-7Search in Google Scholar

27. Hashemi-Soteh SM, Sarzare F, Merat F, Salehifar E, Shiran MR. Frequencies of three CYP2D6 nonfunctional alleles (CYP2D6*3, *4, and *6) within an Iranian population (Mazandaran). Genet Test Mol Biomark 2011;15:821–5.10.1089/gtmb.2011.0033Search in Google Scholar PubMed

28. Shahriary G, Galehdari H, Jalali A, Zanganeh F, Reza Alavi S, Reza Aghanoori M. CYP2E1*5B, CYP2E1*6, CYP2E1*7B, CYP2E1*2, and CYP2E1*3 allele frequencies in Iranian populations. Asian Pac J Cancer Prev 2012;13:6505–10.10.7314/APJCP.2012.13.12.6505Search in Google Scholar PubMed

29. Moasser E, Kazemi-Nezhad SR, Saadat M, Azarpira N. Study of the association between glutathione S-transferase (GSTM1, GSTT1, GSTP1) polymorphisms with type II diabetes mellitus in southern of Iran. Mol Biol Rep 2012;39:10187–92.10.1007/s11033-012-1893-4Search in Google Scholar PubMed

30. Tanira MO, Al-Mukhaini MK, Al-Hinai AT, Al Balushi Ka, Ahmed IS. Frequency of CYP2C9 genotypes among Omani patients receiving warfarin and its correlation with warfarin dose. Community Genet 2007;10:32–7.10.1159/000096279Search in Google Scholar PubMed

31. Tanira MO, Simsek M, Al Balushi K, Al Lawatia K, Al Barawani H, Bayoumi RA. Distribution of arylamine N-acetyltransferase 2 (NAT2) genotypes among Omanis. J Sci Res Med Sci 2003;5:9–14.Search in Google Scholar

32. Saeed H, Alanazi M, Nounou H, Shalaby M, Semlali A, Azzam N, et al. Cytochrome P450 1A1, 2E1 and GSTM1 gene polymorphisms and susceptibility to colorectal cancer in the Saudi Population. Asian Pac J Cancer Prev 2013;14:3761–68.10.7314/APJCP.2013.14.6.3761Search in Google Scholar

33. Alzahrani A, Ragia G, Hanieh H, Manolopoulos V. Genotyping of CYP2C9 and VKORC1 in the Arabic Population of Al-Ahsa, Saudi Arabia. Biomed Res Int 2013;2013:315980.10.1155/2013/315980Search in Google Scholar PubMed PubMed Central

34. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, et al. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 1997;7:59–64.10.1097/00008571-199702000-00008Search in Google Scholar PubMed

35. McLellan R, Oscarson M, Seidegard J, Price Evans D, Ingelmans-Sundberg M. Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 1997;7:187–91.10.1097/00008571-199706000-00003Search in Google Scholar PubMed

36. Al-Dayel F, Al-Rasheed M, Ibrahim M, Bu R, Bavi P, Abubaker J, et al. Polymorphisms of drug-metabolizing enzymes CYP1A1, GSTT and GSTP contribute to the development of diffuse large B-cell lymphoma risk in the Saudi Arabian population. Leuk Lymphoma 2008;49:122–9.10.1080/10428190701704605Search in Google Scholar PubMed

37. Bu R, Gutiérrez MI, Al-Rasheed M, Belgaumi A, Bhatia K. Variable drug metabolism genes in Arab population. Pharmacogenomics J 2004;4:260–6.10.1038/sj.tpj.6500251Search in Google Scholar PubMed

38. Ouerhani S, Cherif N, Bahri I, Safra I, Menif S, Abbes S. Genetic polymorphisms of NQO1, CYP1A1 and TPMT and susceptibility to acute lymphoblastic leukemia in a Tunisian population. Mol Biol Rep 2013;40:1307–14.10.1007/s11033-012-2174-ySearch in Google Scholar PubMed

39. Silan C, Tamer Dogan O, Silan F, Mutlu Kukulguven F, Asgun H, Ozdemir S, et al. The prevalence of VKORC1 1639 G>A and CYP2C9*2*3 genotypes in patients that requiring anticoagulant therapy in Turkish population. Mol Biol Rep 2012;39:11017–22.10.1007/s11033-012-2004-2Search in Google Scholar PubMed

40. Serin A, Canan H, Alper B, Gulmen M. The frequencies of mutated alleles of CYP2D6 gene in a Turkish population. Forensic Sci Int 2012;222:332–4.10.1016/j.forsciint.2012.07.012Search in Google Scholar PubMed

41. Gönül N, Kadioglu E, Kocabaş NA, Ozkaya M, Karakaya AE, Karahalil B. The role of GSTM1, GSTT1, GSTP1, and OGG1 polymorphisms in type 2 diabetes mellitus risk: a case-control study in a Turkish population. Gene 2012;505:121–7.10.1016/j.gene.2012.05.025Search in Google Scholar PubMed

42. Ulusoy G, Arinç E, Adali O. Genotype and allele frequencies of polymorphic CYP2E1 in the Turkish population. Arch Toxicol 2007;81:711–8.10.1007/s00204-007-0200-ySearch in Google Scholar PubMed

43. Aynacioglu AS, Cascorbi I, Mrozikiewicz PM, Roots I. Arylamine N-acetyltransferase (NAT2) genotypes in a Turkish population. Pharmacogenetics 1997;7:327–31.10.1097/00008571-199708000-00008Search in Google Scholar PubMed

44. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2012;92:414–17.10.1038/clpt.2012.96Search in Google Scholar PubMed PubMed Central

45. Database of Single Nucleotide Polymorphisms (dbSNP). Bethesda (MD): National Center for Biotechnology Information, National Library of Medicine. Available at: http://www.ncbi.nlm.nih.gov/SNP/.Search in Google Scholar

46. Cascorbi I, Drakoulis N, Brockmöller J, Maurer A, Sperling K, Roots I. Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity. Am J Hum Genet 1995;57:581–92.Search in Google Scholar

47. Haroun F, Hatoum H, Bazarbachi A, Shamseddine A, Salem Z, Taher A, et al. The role of CYP2B6 genetic polymorphisms in predicting toxicity from cyclophosphamide based therapy in Lebanese patients with breast cancer or Non-Hodgkin′s Lymphoma [abstract]. Presented at: The International Union of Basic and Clinical Pharmacology 2010:17–23.Search in Google Scholar

48. Esmerian M, Mitri Z, Habbal M, Geryess E, Zaatari G, Alam S, et al. Influence of CYP2C9 and VKORC1 polymorphisms on warfarin and acenocoumarol in a sample of Lebanese people. J Clin Pharmacol 2011;51:1418–28.10.1177/0091270010382910Search in Google Scholar PubMed

49. El-Halabi M, Zgheib NK, Mansour N, Malli A, Ghaith O, Mahfouz R, et al. CYP2C19 genetic polymorphism, rabeprazole and esomeprazole have no effect on the antiplatelet action of clopidogrel. J Cardiovasc Pharmacol 2013;62:41–9.10.1097/FJC.0b013e31828ecf44Search in Google Scholar PubMed

50. Tfayli A, Zgheib NK, Holail Y, Habbal MZ, Halawi R, El Saghir N, et al. The influence of CYP2D6 genetic polymorphisms on variability of tamoxifen metabolism in the Lebanese breast cancer population [abstract]. Presented at: 34th San Antonio Breast Cancer (SABC) meeting; 2011:6–10.10.1158/0008-5472.SABCS11-P4-01-16Search in Google Scholar

51. Zgheib NK, Mitri Z, Geryess E, Noutsi P. Cytochrome P4502E1 (CYP2E1) genetic polymorphisms in a Lebanese population: frequency distribution and association with morbid diseases. Genet Test Mol Biomarkers 2010;14:393–7.10.1089/gtmb.2009.0193Search in Google Scholar PubMed

52. Zgheib NK, Arabi A, Mahfouz R, El-hajj Fuleihan G. CYP2R1 genetic polymorphisms are associated with lower 25-hydroxy vitamin D levels in Lebanese subjects [abstract]. Presented at: 11th EACPT Congress 2013:28–31.10.1016/j.clinthera.2013.07.003Search in Google Scholar

53. Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90:625–9.10.1038/clpt.2011.185Search in Google Scholar PubMed PubMed Central

54. Isma′eel H, Sakr G, Habib R, Almedawar M, Zgheib NK, Elhajj I. Improved accuracy of anticoagulant dose prediction using a pharmacogenetic and artificial neural network based method. Eur J Clin Pharmacol 2013 Dec 3. [Epub ahead of print].10.1007/s00228-013-1617-2Search in Google Scholar PubMed

55. US Food and Drug Administration. Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s055lbl.pdf.Search in Google Scholar

56. Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res 2011;128:307–16.10.1016/j.thromres.2011.04.010Search in Google Scholar PubMed

57. Arabi A, El Rassi R, El-Hajj Fuleihan G. Hypovitaminosis D in developing countries – prevalence, risk factors and outcomes. Nat Rev Endocrinol 2010;6:550–61.10.1038/nrendo.2010.146Search in Google Scholar PubMed

58. Bischoff-Ferrari H. Vitamin D – from essentiality to functionality. Int J Vitam Nutr Res 2012;82:321–6.10.1024/0300-9831/a000126Search in Google Scholar PubMed

59. Zgheib NK, Akra M, Aridi C, Saab R, Abboud M, Mahfouz R, et al. The role of pharmacogenetics in the treatment of Lebanese patients with childhood acute lymphoblastic leukemia [abstract]. Presented at: 44th SIOP Congress; 2012:5–8.Search in Google Scholar

60. Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, et al. Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010;102:1003–9.10.1038/sj.bjc.6605587Search in Google Scholar PubMed PubMed Central

61. Afsar NA, Ufer M, Haenisch S, Remmler C, Mateen A, Usman A, et al. Relationship of drug metabolizing enzyme genotype to plasma levels as well as myelotoxicity of cyclophosphamide in breast cancer patients. Eur J Clin Pharmacol 2012;68:389–95.10.1007/s00228-011-1134-0Search in Google Scholar PubMed

62. Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. J Am Med Assoc 2009;302:1429–36.10.1001/jama.2009.1420Search in Google Scholar PubMed PubMed Central

63. Brauch H, Chowbay B, Eccles D, Mürdter T, Saladores P, Schroth W, et al. Genetic and non-genetic determinants of tamoxifen metabolism predict drug concentrations and clinical outcomes in premenopausal patients with early breast cancer. Presented at: Annual Meeting of the American Association for Cancer Research (AACR); 2013:6–10.Search in Google Scholar

64. Sissung TM, English BC, Venzon D, Figg WD, Deeken JF. Clinical pharmacology and pharmacogenetics in a genomics era: the DMET platform. Pharmacogenomics 2010;11:89–103.10.2217/pgs.09.154Search in Google Scholar PubMed PubMed Central

65. Awada Z, Haider S, Tfayli A, Bazarbachi A, El-Saghir NS, Salem Z, et al. Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS 2013;17: 353–67.10.1089/omi.2013.0019Search in Google Scholar PubMed

66. Antoun J, Zgheib NK, Ashkar K. Education may improve the underutilization of genetic services by Middle Eastern primary care practitioners. Genet Test Mol Biomark 2010;14:447–54.10.1089/gtmb.2010.0021Search in Google Scholar PubMed

67. Zgheib NK, Arawi T, Mahfouz RA, Sabra R. Attitudes of health care professionals toward pharmacogenetic testing. Mol Diagn Ther 2011;15:115–22.10.1007/BF03256401Search in Google Scholar PubMed

68. Ghaddar F, Cascorbi I, Zgheib NK. Clinical implementation of pharmacogenetics: a non-representative explorative survey to participants of WorldPharma 2010. Pharmacogenomics 2011;12:1051–9.10.2217/pgs.11.42Search in Google Scholar PubMed

69. Haddow JE, Palomaki GE. ACCE: a model process for evaluating data on emerging genetic tests. In: Khoury M, Little J, Burke W, editors. Human genome epidemiology: a scientific foundation for using genetic information to improve health and prevent disease. USA: Oxford University Press, 2003: 217–33.Search in Google Scholar

70. Relling MV, Klein TE. CPIC: Clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharmacol Ther 2011;89:464–7.10.1038/clpt.2010.279Search in Google Scholar PubMed PubMed Central

Received: 2013-10-29
Accepted: 2013-12-12
Published Online: 2014-1-11
Published in Print: 2014-6-1

©2014 by Walter de Gruyter Berlin/Boston

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