Skip to main content

Advertisement

SpringerLink
Log in

Genetic polymorphism of CYP2C19 in Maharashtrian population

  • GENETIC EPIDEMIOLOGY
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

Inter-individual variability in drug response is well known. Genetic polymorphism in genes encoding drug-metabolizing enzymes results in variation in drug metabolism and in turn drug response. The cytochrome P450 enzymes (CYP) play a central role in the metabolism of many therapeutic agents. CYP2C19 gene polymorphism is widely studied in Caucasians, African, and Oriental populations; however, far less is known about other ethnic groups such as Indians. Indian population is an inter-mixture of the Aryan, Dravidian, Kolarain, and the Mongoloid races. CYP2C19 gene polymorphism is reported in North Indian and South Indian populations yet not much is known about Maharashtrian population of Australoid-Europoid origin residing in Western India. This is the first report on CYP2C19 allele and genotype frequencies in Maharashtrian population. In this study, genotypes of major allelic variants of CYP2C19 gene in 139 unrelated healthy Maharashtrian subjects was determined and their frequencies were compared with previously studied Indian and other populations. Meta-analysis revealed that the study population is distinct from Caucasians, Africans and some of the Asian populations and significant heterogeneity exists among Indian subpopulations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

CI:

Confidence interval

CYP:

Cytochrome P450 enzyme

DNA:

Deoxyribonucleic acid

dNTPs:

Deoxyribonucleotide triphosphates

EDTA:

Ethylenediammine tetra acetic acid

EM:

Extensive metabolizer

PCR:

Polymerase chain reaction

PM:

Poor metabolizer

rs no:

Reference SNP no

RFLP:

Restriction fragment length polymorphism

References

  1. Evans WE. Pharmacogenomics: marshalling the human genome to individualize drug therapy. Gut 2003;52 Suppl II:ii10–8.

    Google Scholar 

  2. Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med 2003;348:538–49.

    Article  PubMed  CAS  Google Scholar 

  3. Meyer UA. Pharmacogenetics. The slow, the rapid and the ultrarapid. Proc Natl Acad Sci USA 1994;91:1983–4.

    Article  PubMed  CAS  Google Scholar 

  4. Goldstein JA, de Morais SMF. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 1994;4:285–99.

    Article  PubMed  CAS  Google Scholar 

  5. Daly AK. Molecular basis of polymorphic drug metabolism. J Mol Med 1995;73:539–53.

    Article  PubMed  CAS  Google Scholar 

  6. de Morais SMF, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994;269:15419–22.

    PubMed  Google Scholar 

  7. de Morais SMF, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of S-mephenytoin metabolism in Japanese. Mol pharmacol 1994;96:594–8.

    Google Scholar 

  8. Kubota T, Chiba K, Ishizaki T. Genotyping of S-mephenytoin 4’ hydroxylation in an extended Japanese population. Clin Pharmacol Ther 1996;60:661–6.

    Article  PubMed  CAS  Google Scholar 

  9. Alvan G, Bechtel P, Iselius L, Gundert-Remy U. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990;39:533–7.

    Article  PubMed  CAS  Google Scholar 

  10. Xiao ZS, Golstein JA, Xie HG, Blaisdell J, Wang W, Jiang CH, Yan FX, He N, Huang SL, Xu ZH, Zhou HH. Differences in the incidence of CYP2C19 polymorphism affecting the S-mephenyotin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther 1997;281:604–9.

    PubMed  CAS  Google Scholar 

  11. Sohn D-R, Kusaka M, Ishizaki T, Shin S-G, Jang I-J, Shin J-G, Chiba K. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther 1992;52:160–9.

    Article  PubMed  CAS  Google Scholar 

  12. Kaneko A, Kaneko O, Taleo G, Bjorkman A, Kobayakawa T. High frequencies of CYP2C19 mutations and poor metabolism of proguanil in Vanuatu. Lancet 1997;349:921–2.

    Article  PubMed  CAS  Google Scholar 

  13. Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM, Wang KY, Reviriego J, Iselius L, Sjoqvist F. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylation of debrisoquine and S-mephenytoin. Clin Pharmacol Ther 1992;51:388–97.

    Article  PubMed  CAS  Google Scholar 

  14. Lamba JK, Dhiman RK, Kohli KK. CYP2C19 genetic mutations in North Indians. Clin Pharmacol Ther 2000;68:328–35.

    Article  PubMed  CAS  Google Scholar 

  15. Rosemary J, Adithan C, Soya S, Gerard N, Chanolean S, Abraham B, Satyanarayanamoorthy K, Peter A, Rajagopal K. CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in south Indian population. Fundam Clin Pharmacol 2005;19(1):101–5.

    Article  CAS  Google Scholar 

  16. Karve I. ‘Maharashtra-Land & it’s people’ Maharashtra State gazetteers general series. Maharashtra State: Bombay Directorate of Government Printing, Stationary & publications; 1968.

    Google Scholar 

  17. Miller SA, Dykes DD. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16(3):1215.

    Article  PubMed  CAS  Google Scholar 

  18. Goldstein JA, Blaisdell J. Genetic tests which identify the principle defects in CYP2C19 responsible for the polymorphism in Mephenytoin metabolism. Methods enzymol 1996;272:210–7.

    Article  PubMed  CAS  Google Scholar 

  19. Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989;43:53–76.

    Article  PubMed  CAS  Google Scholar 

  20. Bertilsson L. Geographic/interracial differences in polymorphic drug oxidation: current state of the knowledge of cytochrome P450 (CYP)2D6 and 2C19. Clin Pharmacokinet 1995;29:192–209.

    PubMed  CAS  Google Scholar 

  21. Ruas JC, Lechner MC. Allele frequency of CYP2C19 in a Portoguese population. Pharmacogenetics 1997;7:333–5.

    Article  PubMed  CAS  Google Scholar 

  22. Kaisary A, Smith P, et al. Genetic predisposition to bladder cancer: ability to hydroxylate debrisoquine and mephenytoin as risk factors. Cancer Res 1987;47:5488–93.

    PubMed  CAS  Google Scholar 

  23. Tsuneoka Y, Fukushima K, Matsu Y, Ichikwa Y, Watanabe Y. Genetic analysis of the CYP2C19 gene in the Japanese population. Life Sci 1996;59:1711–15.

    Article  PubMed  CAS  Google Scholar 

  24. May DG, Black CM, Olsen NJ, et al. Scleroderma is associated with differences in individual routes of drug metabolism: a study with dapsone, debrisoquine, and mephenytoin. Clin Pharmacol Ther 1990;48:286–95.

    Article  PubMed  CAS  Google Scholar 

  25. Flockhart DA, Clauw DJ, Sale EB, Hewett J, Woosley RL. Pharmacogenetic characteristics of the eosinophilia-myalgia syndrome. Clin Pharmacol Ther 1994;56:398–405.

    Article  PubMed  CAS  Google Scholar 

  26. Chang M, Dahl ML, Tybring G, Gotharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 1995;5(6):358–63.

    Article  PubMed  CAS  Google Scholar 

  27. Futura T, Ohashi K, Kamata T, et al. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med 1998;129:1027–30.

    Google Scholar 

  28. Wan J, Xia H, He N, et al. The elimination of diazepam in Chinese subjects is dependant on the mephenytoin oxidation phenotype. Br J Clin Pharmacol 1996;42:471–4.

    Article  PubMed  CAS  Google Scholar 

  29. Qin XP, Xie HG, Wang W, et al. Effect of gene dosage of Cgamma19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther 1999;66:642–6.

    PubMed  CAS  Google Scholar 

  30. Sogawa K, Gotoh O, Kawajiri K, et al. Complete nucleotide sequence of a methylcholanthrene-inducible cytochrome pP-450 (P-450d) gene in rat. J Biol Chem 1985;260:5026–31.

    PubMed  CAS  Google Scholar 

  31. Lillibridge JH, Liang BH, Kerr BM, et al. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos 1998;26:609–16.

    PubMed  CAS  Google Scholar 

  32. Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2002;53(4):408–9.

    Article  Google Scholar 

  33. Birkett DJ, Rees D, Andersson T, Gonzalez FJ, Miners JO, Veronese ME. In vitro proguanil activation by human liver microsomes is mediated by CYP3Aisoforms as by S-mephenytoin hydroxylase. Br J Clin Pharmacol 1994;37:413–20.

    PubMed  CAS  Google Scholar 

  34. Funck-Brentano C, Becquemont L, Leneveu A, Roux A, Jallion P, Beaune P. Inhibition by omeprazole of proguanil metabolism: mechanism of the interaction in vitro and prediction of in vivo results from the experiments. J Pharmacol Exp Ther 1997;280:730–8.

    PubMed  CAS  Google Scholar 

  35. Xie HG, Kim RB, Stein CM, Wilkinson GR, Wood AJ. Genetic polymorphism of (S)-mephenytoin 4′-hydroxylation in populations of African descent. Br J Clin Pharmacol 1999;48(3):402–8.

    Article  PubMed  CAS  Google Scholar 

  36. Yamada S, Onda M, Kato S, et al. Genetic differences in CYP2C19 single nucleotide polymorphisms among four Asian populations. J Gastroenterol 2001;36:669–72.

    Article  PubMed  CAS  Google Scholar 

  37. Takakubo F, Kuwano A, Kondo I. Evidence that poor metabolizers of (s)-mephenytoin could be identified by haplotypes of CYP2C19 in japanese. Pharmacogenetics 1996;36:669–72.

    Google Scholar 

  38. Roh HK, Dahl ML, Tybring G, Yamada H, Cha YN, Bertilsson L. CYP2C19 genotype and phenotype in determined by omeprazole in a Korean population. Pharmacogentics 1996;6:547–51.

    Article  CAS  Google Scholar 

  39. Tassaneeyakul W, Mahatthanatrakul W, Niwatananun K, Bangchange K, Tawalee A, Krikreangsak N, Cykleng U, Tassaneeyakul W. CYP2C19 Genetic polymorphism in Thai, Burmese and Karen populations. Drug Metab Pharmacokinet 2006;21(4):286–90.

    Article  PubMed  CAS  Google Scholar 

  40. Yang YS, Wong LP, Lee TC, Mustafa AM, Mohamed Z, Lang CC. Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects. Br J Clin Pharmacol 2004;58(3):332–5.

    Article  PubMed  CAS  Google Scholar 

  41. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, Evans DA. 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(1):59–64.

    Article  PubMed  CAS  Google Scholar 

  42. Aynacioglu AS, Sachse C, Bozkurt A, Kortunay S, Nacak M, Schröder T, Kayaalp SO, Roots I, Brockmöller J. Low frequencyof defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther 1999;66:185–92.

    PubMed  CAS  Google Scholar 

  43. Sviri S, Shpizen S, et al. Phenotypic—genotypic analysis of CYP2C19 in the Jewish Israeli population. Clin Pharmacol Ther 1999;65:275–82.

    Article  PubMed  CAS  Google Scholar 

  44. Kaneko A, Lum JK, Yaviong L, Takahashi N, Ishizaki T, Bertilsson L, Kobayakawa T, Bjorkman A. High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands. Pharmacogenetics 1999;9(5):581–90.

    Article  PubMed  CAS  Google Scholar 

  45. Griese EU, Ilett KF, Kitteringham NR, et al. Allele and genotype frequencies of polymorphic cytochromes P4502D6, 2C19 and 2E1 in Aborigines from Western Australia. Pharmacogenetics 2001;11:69–76.

    Article  PubMed  CAS  Google Scholar 

  46. Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, Brockmoller J, Frotschl R, Kopke K, Gerloff T, Chernov JN, Roots I. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 2003;59(4):30312.

    Article  CAS  Google Scholar 

  47. Scordo MG, Caputi AP, D’Arrigo C, Fava G, Spina E. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Eur J Clin Pharmacol 2003;59(4):303–12.

    Article  CAS  Google Scholar 

  48. Bo_ina N, Graniæ P, Laliæ Z, Tramišak I, Lovriæ M, Stavljeniæ-Rukavina A. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian Population. Roatian Med J 2003;44(4):425–8.

    Google Scholar 

  49. Allabi AC, Gala JL, Desager JP, Heusterspreute M, Horsmans Y. Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations. Br J Clin Pharmacol 2003;56:653–657.

    Article  PubMed  CAS  Google Scholar 

  50. Ruas JL, Lechner MC. Allele frequency of CYP2C19 in a Portuguese population. Pharmacogenetics 1997;7:333–5.

    Article  PubMed  CAS  Google Scholar 

  51. Nowak MP, Sellers EM, Tyndale RF. Canadian Native Indians exhibit unique CYP2A6 and CYP2C19 mutant allele frequencies. Clin Pharmacol Ther 1998;64:378–83.

    Article  PubMed  CAS  Google Scholar 

  52. Bravo-Villalta H, Yamamoto K, Nakamura K, Baya A, Okada Y, Horiuchi R. Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study. Eur J Clin Pharmacol 2005;61:179–84.

    Article  PubMed  CAS  Google Scholar 

  53. Halling J, Petersen MS, Damkier P, Nielsen F, Grandjean P, Pa´ l Weihe Lundgren S, Lundblad MS, Brøsen K. Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population. Eur J Clin Pharmacol 2005;61:491–97.

    Article  PubMed  CAS  Google Scholar 

  54. Yamada H, Dahl M-L, Lannfelt L, Viitanen M, Winblad B, SjoÈ qvist F. CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol 1998;54:479–81.

    Article  PubMed  CAS  Google Scholar 

  55. Bathum L, Andersen-Ranberg K, Boldsen J, Brùsen K, Jeune B. Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevity Role of CYP2D6 and CYP2C19 in longevity. Eur J Clin Pharmacol 1998;54:427–30.

    Article  PubMed  CAS  Google Scholar 

  56. Xie HG, Kim RB, Stein CM, Wilkinson GR, Wood AJ. Genetic polymorphism of (S)-mephenytoin 4′-hydroxylation in populations of African descent. Br J Clin Pharmacol 1999;48(3):402–8.

    Article  PubMed  CAS  Google Scholar 

  57. Hamdy SI, Hiratsuka M, Narahara K, Enany M, Moursi N, Ahmed MS, Mizugaki M. 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.

    Article  PubMed  CAS  Google Scholar 

  58. Persson I, Aklillu E, Rodrigues F, Bertilsson L, Ingelman-Sundberg M. S-mephenytoin hydroxylation phenotype and CYP2C19 genotype among Ethiopians. Pharmacogenetics 1996;6:521–6.

    Article  PubMed  CAS  Google Scholar 

  59. Herrlin K, Massele AY, Jande M, Alm C, Tybring G, Abdi YA, Wennerholm A, Johansson I, Dahl ML, Bertilsson L, Gustafsson LL. Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin Pharmacol Ther 1998;64(4):391–401.

    Article  PubMed  CAS  Google Scholar 

  60. Masimirembwa C, Bertilsson L, Johansson I, Hasler JA, Ingelman-Sundberg M. Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population in Zimbabwe. Clin Pharmacol Ther 1995;57:656–1.

    Article  PubMed  CAS  Google Scholar 

  61. Dandara C, Masimirembwa CM, Magimba A, et al. Genetic polymorphism of CYP2D6, CYP2C19 in East, Southern African populations including psychiatric patients. Eur J Clin Pharmacol 2001;75:11–7.

    Article  Google Scholar 

Download references

Acknowledgments

Authors are thankful to Council for Scientific and Industrial Research, Technology and Business Development Division, New Delhi, India, for financial assistance. We also thank Dr. Girish Tillu for his help in recruiting subjects and blood collection, Dr. Aarti Kaulgekar for Anthropological inputs, and Mr. Amrutesh Puranik for his help in statistical analysis.

Author information

Authors and Affiliations

  1. Bioprospecting Laboratory, Interdisciplinary School of Health Sciences, University of Pune, Pune, 411007, Maharashtra, India

    Yogita Ghodke, Kalpana Joshi, Yashendra Arya, Anjali Radkar, Aditi Chiplunkar, Pooja Shintre & Bhushan Patwardhan

Authors
  1. Yogita Ghodke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kalpana Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yashendra Arya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anjali Radkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aditi Chiplunkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pooja Shintre
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bhushan Patwardhan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kalpana Joshi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ghodke, Y., Joshi, K., Arya, Y. et al. Genetic polymorphism of CYP2C19 in Maharashtrian population. Eur J Epidemiol 22, 907–915 (2007). https://doi.org/10.1007/s10654-007-9196-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-007-9196-0

Keywords

Search

Navigation