Skip to main content
SpringerLink
Log in

Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

Several reports of CYP2C genetic polymorphism demonstrate its potential clinical role in determining both inter-individual and inter-ethnic differences in drug efficacy. We estimated the distribution of CYP2C9 and CYP2C19 common variants in the Bolivian population (a South American population), and compared these data with those from Asian, African, Caucasian and Oceanian populations.

Methods

Genomic DNA was obtained from 778 unrelated healthy volunteers from Bolivia. The genotypic status of CYP2C9 and CYP2C19 was determined by means of polymerase chain reaction–restriction fragment length polymorphism.

Results

Allelic and genotypic frequencies of CYP2C9 and CYP2C19 were determined for the Bolivian population, and comparison of the data with other ethnic groups revealed a lower CYP2C9*2 frequency (4.8%) than in Caucasians, but a higher frequency than in Asians; frequencies of CYP2C9*3 (3.0%) and CYP2C9 (0.4%) poor metabolizers (PMs) were similar to those seen in Asian populations. Frequencies of CYP2C19*2 (7.8%), CYP2C19*3 (0.1%), and CYP2C19 PMs (1.0%) in the Bolivian population were for the most part lower than in Caucasian, Asian, Oceanian and African populations.

Conclusion

This is the first study to investigate a South American population for genetic polymorphism in the CYP2C subfamily. The Bolivian population differs from most other ethnic groups in the incidence of CYP2C9 and CYP2C19 common variants that might be influenced by its admixture characteristics.

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

Similar content being viewed by others

References

  1. Meehan RR, Gosden JR, Rout D et al (1988) Human cytochrome P-450 PB-I: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet 42:26–37

    Google Scholar 

  2. Gray IC, Nobile C, Muresu R, Ford S, Spurr NK (1995) A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics 28:328–332

    Google Scholar 

  3. Goldstein JA, de Morais SM (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285–299

    CAS  PubMed  Google Scholar 

  4. Miners JO, Birkett DJ (1998) Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 45:525–538

    Google Scholar 

  5. Takahashi H, Echizen H (2001) Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 40:587–603

    Google Scholar 

  6. Lee CR, Goldstein JA, Pieper JA (2002) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12:251–263

    Google Scholar 

  7. Goldstein JA (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 52:349–355

    Google Scholar 

  8. Correia MA (2001) Drug biotransformation. In: Katzung BG (ed) Basic & clinical pharmacology. Lange Medical Books/McGraw Hill, New York, pp 51–63

    Google Scholar 

  9. Bertilsson L (1995) Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 29:192–209

    Google Scholar 

  10. Wedlund PJ (2000) The CYP2C19 enzyme polymorphism. Pharmacology 61:174–183

    Google Scholar 

  11. Desta Z, Zhao X, Shin JG, Flockhart DA (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41:913–958

    Google Scholar 

  12. Home page of the human cytochrome P450 (CYP) allele nomenclature committee. http://www.imm.ki.se/CYPalleles

  13. Sullivan-Klose TH, Ghanayem BI, Bell DA et al (1996) The role of the CYP2C9–Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6:341–349

    Google Scholar 

  14. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR (1994) Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 4:39–42

    Google Scholar 

  15. Crespi CL, Miller VP (1997) The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics 7:203–210

    Google Scholar 

  16. de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419–15422

    PubMed  Google Scholar 

  17. de Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA (1994) Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 46:594–598

    PubMed  Google Scholar 

  18. Kimura M, Ieiri I, Mamiya K, Urae A, Higuchi S (1998) Genetic polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a Japanese population. Ther Drug Monit 20:243–247

    Google Scholar 

  19. Goldstein JA, Ishizaki T, Chiba K et al (1997) Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 7:59–64

    Google Scholar 

  20. Yamada S, Onda M, Kato S et al (2001) Genetic differences in CYP2C19 single nucleotide polymorphisms among four Asian populations. J Gastroenterol 36:669–672

    Google Scholar 

  21. Takakubo F, Kuwano A, Kondo I (1996) Evidence that poor metabolizers of (S)-mephenytoin could be identified by haplotypes of CYP2C19 in Japanese. Pharmacogenetics 6:265–267

    Google Scholar 

  22. Garcia-Barcelo M, Chow LY, Kum Chiu HF et al (1999) Frequencies of defective CYP2C19 alleles in a Hong Kong Chinese population: detection of the rare allele CYP2C19*4. Clin Chem 45:2273–2274

    Google Scholar 

  23. He N, Yan FX, Huang SL et al (2002) CYP2C19 genotype and S-mephenytoin 4′-hydroxylation phenotype in a Chinese Dai population. Eur J Clin Pharmacol 58:15–18

    Google Scholar 

  24. Roh HK, Dahl ML, Tybring G, Yamada H, Cha YN, Bertilsson L (1996) CYP2C19 genotype and phenotype determined by omeprazole in a Korean population. Pharmacogenetics 6:547–551

    Google Scholar 

  25. Xie HG, Stein CM, Kim RB, Wilkinson GR, Flockhart DA, Wood AJ (1999) Allelic, genotypic and phenotypic distributions of S-mephenytoin 4′-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 9:539–549

    CAS  PubMed  Google Scholar 

  26. Tamminga WJ, Wemer J, Oosterhuis B, de Zeeuw RA, de Leij LF, Jonkman JH (2001) The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers. Eur J Clin Pharmacol 57:717–722

    Google Scholar 

  27. Ibeanu GC, Goldstein JA, Meyer U et al (1998) Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther 286:1490–1495

    Google Scholar 

  28. Aynacioglu AS, Sachse C, Bozkurt A et al (1999) Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther 66:185–192

    Google Scholar 

  29. Ruas JL, Lechner MC (1997) Allele frequency of CYP2C19 in a Portuguese population. Pharmacogenetics 7:333–335

    Google Scholar 

  30. Gaedigk A, Casley WL, Tyndale RF, Sellers EM, Jurima-Romet M, Leeder JS (2001) Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations. Can J Physiol Pharmacol 79:841–847

    Google Scholar 

  31. Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR (1996) Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 6:429–439

    Google Scholar 

  32. Taube J, Halsall D, Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk over-anticoagulation in patients on long-term treatment. Blood 96:1816–1819

    CAS  PubMed  Google Scholar 

  33. Cascorbi I, Ackermann E, Sachse C, Brockmoller J, Roots I (1998) A novel CYP2C9 intron 2T/C transition and linkage to mutations Leu359 and Cys144. Clin Pharmacol Ther 63:198

    Google Scholar 

  34. Burian M, Grösch S, Tegeder I, Geisslinger G (2002) Validation of a new fluorogenic real-time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population. Br J Clin Pharmacol 54:518–521

    Google Scholar 

  35. Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M (2001) Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 52:447–450

    Article  Google Scholar 

  36. Garcia-Martin E, Martinez C, Ladero JM, Gamito FJ, Agundez JA (2001) High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol 57:47–49

    Google Scholar 

  37. Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjöqvist F (1999) Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 254:628–631

    Google Scholar 

  38. Nasu K, Kubota T, Ishizaki T (1997) Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics 7:405–409

    Google Scholar 

  39. Takahashi H, Kashima T, Nomizo Y et al (1998) Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Ther 63:519–528

    Google Scholar 

  40. Yoon YR, Shon JH, Kim MK et al (2001) Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br J Clin Pharmacol 51:277–280

    Google Scholar 

  41. Web site of “Instituto Nacional de Estadística, Bolivia”. http://www.ine.gov.bo

  42. The World Factbook. http://www.odci.gov/cia/publications/factbook

  43. Bolivia. Country Studies. Federal Research Division, Library of Congress. http://lcweb2.loc.gov/frd/cs/botoc.html

  44. Pueblos Indigenas y originarios. Viceministerio de Cultura Bolivia. http://www.bolivia.com/empresas/cultura/Pueblos_Indigenas/index.asp

  45. Plaza-Martinez P, Carvajal-Carvajal J (1985) Etnias y lenguas de Bolivia. Editorial Instituto de Cultura, La Paz

    Google Scholar 

  46. Aynacioglu AS, Brockmöller J, Bauer S et al (1999) Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48:409–415

    Google Scholar 

  47. Hamdy SI, Hiratsuka M, Narahara K et al (2002) Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYP) in the Egyptian population. Br J Clin Pharmacol 53:596–603

    Google Scholar 

  48. Nowak MP, Sellers EM, Tyndale RF (1998) Canadian Native Indians exhibit unique CYP2A6 and CYP2C19 mutant allele frequencies. Clin Pharmacol Ther 64:378–383

    Google Scholar 

  49. Chang M, Dahl ML, Tybring G, Götharson E, Bertilsson L (1995) Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 5:358–363

    Google Scholar 

  50. Sviri S, Shpizen S, Leitersdorf E, Levy M, Caraco Y (1999) Phenotypic-genotypic analysis of CYP2C19 in the Jewish Israeli population. Clin Pharmacol Ther 65:275–282

    Google Scholar 

  51. Persson I, Aklillu E, Rodrigues F, Bertilsson L, Ingelman-Sundberg M (1996) S-mephenytoin hydroxylation phenotype and CYP2C19 genotype among Ethiopians. Pharmacogenetics 6:521–526

    Google Scholar 

  52. Kaneko A, Lum JK, Yaviong J et al (1999) High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands. Pharmacogenetics 9:581–590

    Google Scholar 

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

    Google Scholar 

  54. Cavalli-Sforza LL, Piazza A, Menozzi P, Mountain J (1988) Reconstruction of human evolution: bringing together genetic, archaeological, and linguistic data. Proc Natl Acad Sci U S A 85:6002–6006

    Google Scholar 

  55. Furuta T, Ohashi K, Kamata T et al (1998) Effect of genetic differences in Omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Inter Med 129:1027–1030

    Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, 371-8511, Japan

    Heydy V. Bravo-Villalta, Koujirou Yamamoto, Katsunori Nakamura, Yuko Okada & Ryuya Horiuchi

  2. Dirección Nacional de Investigación, Universidad Privada del Valle, Campus Universitario—Tiquipaya, Cochabamba, Bolivia

    Ana Bayá

Authors
  1. Heydy V. Bravo-Villalta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koujirou Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katsunori Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana Bayá
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuko Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ryuya Horiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryuya Horiuchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bravo-Villalta, H.V., Yamamoto, K., Nakamura, K. et al. Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study. Eur J Clin Pharmacol 61, 179–184 (2005). https://doi.org/10.1007/s00228-004-0890-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-004-0890-5

Keywords

Search

Navigation