Skip to main content
Springer Nature Link
Log in

Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2C8, CYP2C9, and CYP2C19 genetic polymorphisms. DNA from 282 Spaniard and 297 Ecuadorian subjects were analyzed by either a previously reported pyrosequencing method (CY2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3) or a nested PCR technique (CYP2C19*17). Whereas CYP2C19*17 allele distribution was higher in Ecuadorians than in Spaniards (P < 0.001) and the frequency of CYP2C19*3 was similar in these two populations (P > 0.05), the other allelic variants were detected at significantly lower frequencies in Ecuadorians than in Spaniards (P < 0.05). According to the diplotype distributions, the prevalence of the presumed CYP2C9 and CYP2C8 extensive metabolizers was higher in Ecuadorians than in Spaniards (P < 0.05). Individuals genotyped CYP2C19*1/*17 and *17/*17 who were considered as ultrarapid metabolizers were overrepresented in Ecuadorians in relation to Spaniards (P < 0.001). By contrast, among Ecuadorians no poor metabolizers (PMs) of either CYP2C8 or CYP2C9 were found and only two individuals were CYP2C19 PMs. These data are compatible with a higher CYP2C8, CYP2C9, and CYP2C19 activity in Mestizo Ecuadorians as opposed to Spaniards, which could imply differences in dosage requirements for drugs metabolized by these cytochromes and should also be considered in allele-disease association studies.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. García-Martín E, Martínez C, Ladero JM, Agúndez JA (2006) Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals. Mol Diagn Ther 10(1):29–40

    Article  PubMed  Google Scholar 

  5. Gerbal-Chaloin S, Pascussi JM, Pichard-Garcia L, Daujat M, Waechter F, Fabre JM, Carrère N, Maurel P (2001) Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos 29(3):242–251

    CAS  PubMed  Google Scholar 

  6. Ali ZK, Kim RJ, Ysla FM (2009) CYP2C9 polymorphisms: considerations in NSAID therapy. Curr Opin Drug Discov Devel 12(1):108–114

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Totah RA, Rettie AE (2005) Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Ther 77:341–352

    Article  CAS  PubMed  Google Scholar 

  9. García-Martín E, Martínez C, Tabarés B, Frías J, Agúndez JA (2004) Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther 76:119–127

    Article  PubMed  Google Scholar 

  10. Bahadur N, Leathart JB, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R, Houdt JV, Hendrickx J, Mannens G, Bohets H, Williams FM, Armstrong M, Crespi CL, Daly AK (2002) CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol 64(11):1579–1589

    Article  CAS  PubMed  Google Scholar 

  11. Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116:496–526

    Article  CAS  PubMed  Google Scholar 

  12. Klotz U (2006) Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. Int J Clin Pharmacol Ther 44(7):297–302

    Article  CAS  PubMed  Google Scholar 

  13. Fukasawa T, Suzuki A, Otani K (2007) Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther 32(4):333–341

    Article  CAS  PubMed  Google Scholar 

  14. Arango, J (2004) La inmigración en España en el Siglo XXI. [Immigration in Spain at the beginning of the XXI century]. In: J. Maldonado (ed.) Informe sobre la situación demográfica en España. [Report on the demographic situation in Spain], Spain: Fernando Abril Martorell Foundation, pp 161–186

  15. Martínez C, García-Martín E, Blanco G, Gamito FJ, Ladero JM, Agúndez JA (2005) The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol 59(1):62–69

    Google Scholar 

  16. Sánchez-Diz P, Estany-Gestal A, Aguirre C, Blanco A, Carracedo A, Ibáñez L, Passiu M, Provezza L, Ramos-Ruiz R, Ruiz B, Salado-Valdivieso I, Velasco EA, Figueiras A (2009) Prevalence of CYP2C9 polymorphisms in the south of Europe. Pharmacogenomics J 9(5):306–310

    Google Scholar 

  17. Leskelä S, Jara C, Leandro-García LJ, Martínez A, García-Donas J, Hernando S, Hurtado A, Vicario JC, Montero-Conde C, Landa I, López-Jiménez E, Cascón A, Milne RL, Robledo M, Rodríguez-Antona C (2011) Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity. Pharmacogenomics J 11(2):121–129

    Article  PubMed  Google Scholar 

  18. Alonso-Navarro H, Martínez C, García-Martín E, Benito-León J, García-Ferrer I, Vázquez-Torres P, Puertas I, López-Alburquerque T, Agúndez JA, Jiménez-Jiménez FJ (2006) CYP2C19 polymorphism and risk for essential tremor. Eur Neurol 56(2):119–123

    Article  CAS  PubMed  Google Scholar 

  19. Bernal ML, Sinues B, Johansson I, McLellan RA, Wennerholm A, Dahl ML, Ingelman-Sundberg M, Bertilsson L (1999) Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics 9(5):657–660

    Article  CAS  PubMed  Google Scholar 

  20. Lucotte G, Gérard N, Mercier G (2001) North African genes in Iberia studied by Y-chromosome DNA haplotype 5. Hum Biol 73(5):763–769

    Article  CAS  PubMed  Google Scholar 

  21. Zackrisson AL, Lindblom B, Ahlner J (2010) High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther 88(3):354–359

    Article  CAS  PubMed  Google Scholar 

  22. 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(3):628–631

    Article  CAS  PubMed  Google Scholar 

  23. 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(4):447–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. London SJ, Daly AK, Leathart JB, Navidi WC, Idle JR (1996) Lung cancer risk in relation to the CYP2C9*1/CYP2C9*2 genetic polymorphism among African-Americans and Caucasians in Los Angeles County, California. Pharmacogenetics 6(6):527–533

    Article  CAS  PubMed  Google Scholar 

  25. Nasu K, Kubota T, Ishizaki T (1997) Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics 7(5):405–409

    Article  CAS  PubMed  Google Scholar 

  26. Hong X, Zhang S, Mao G, Jiang S, Zhang Y, Yu Y, Tang G, Xing H, Xu X (2005) CYP2C9*3 allelic variant is associated with metabolism of irbesartan in Chinese population. Eur J Clin Pharmacol 61(9):627–634

    Article  CAS  PubMed  Google Scholar 

  27. Yoon YR, Shon JH, Kim MK, Lim YC, Lee HR, Park JY, Cha IJ, Shin JG (2001) Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br J Clin Pharmacol 51(3):277–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Scordo MG, Caputi AP, D’Arrigo C, Fava G, Spina E (2004) Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res 50(2):195–200

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Fukushima-Uesaka H, Saito Y, Maekawa K, Ozawa S, Hasegawa R, Kajio H, Kuzuya N, Yasuda K, Kawamoto M, Kamatani N, Suzuki K, Yanagawa T, Tohkin M, Sawada J (2005) Genetic variations and haplotypes of CYP2C19 in a Japanese population. Drug Metab Pharmacokinet 20(4):300–307

    Article  PubMed  Google Scholar 

  31. Yamada S, Onda M, Kato S, Matsuda N, Matsuhisa T, Yamada N, Miki M, Matsukura N (2001) Genetic differences in CYP2C19 single nucleotide polymorphisms among four Asian populations. J Gastroenterol 36(10):669–672

    Article  CAS  PubMed  Google Scholar 

  32. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79(1):103–113

    Article  CAS  PubMed  Google Scholar 

  33. Kurzawski M, Gawrońska-Szklarz B, Wrześniewska J, Siuda A, Starzyńska T, Droździk M (2006) Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients. Eur J Clin Pharmacol 62(10):877–880

    Article  CAS  PubMed  Google Scholar 

  34. Santos PC, Soares RA, Santos DB, Nascimento RM, Coelho GL, Nicolau JC, Mill JG, Krieger JE, Pereira AC (2011) CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population. BMC Med Genet 19:12–13

    Article  CAS  Google Scholar 

  35. Sugimoto K, Uno T, Yamazaki H, Tateishi T (2008) Limited frequency of the CYP2C19*17 allele and its minor role in a Japanese population. Br J Clin Pharmacol 65(3):437–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bravo-Villalta HV, Yamamoto K, Nakamura K, Bayá A, Okada Y, Horiuchi R (2005) Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study. Eur J Clin Pharmacol 61(3):179–184

    Article  CAS  PubMed  Google Scholar 

  37. Dorado P, Sosa-Macias MG, Peñas-Lledó EM, Alanis-Bañuelos RE, Wong ML, Licinio J, Lares-Asseff I, Llerena A (2011) CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards. Pharmacogenomics J 11(2):108–112

    Article  CAS  PubMed  Google Scholar 

  38. Roco A, Quiñones L, Agúndez JA, García-Martín E, Squicciarini V, Miranda C, Garay J, Farfán N, Saavedra I, Cáceres D, Ibarra C, Varela N (2012) Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the chilean population: comparison with caucasian and asian populations. Front Genet 2(3):229

  39. Isaza C, Henao J, Martínez JH, Sepúlveda Arias JC, Beltrán L (2007) Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals. BMC Clin Pharmacol 11(7):6

    Article  Google Scholar 

  40. Luo HR, Poland RE, Lin KM, Wan YJ (2006) Genetic polymorphism of cytochrome P450 2C19 in Mexican Americans: a cross-ethnic comparative study. Clin Pharmacol Ther 80(1):33–40

    Article  CAS  PubMed  Google Scholar 

  41. Schirmer M, Toliat MR, Haberl M, Suk A, Kamdem LK, Klein K, Brockmöller J, Nürnberg P, Zanger UM, Wojnowski L (2006) Genetic signature consistent with selection against the CYP3A4*1B allele in non-African populations. Pharmacogenet Genomics 16(1):59-71

    Google Scholar 

  42. Inaba T, Jorge LF, Arias TD (1988) Mephenytoin hydroxylation in the Cuna Amerindians of Panama. Br J Clin Pharmacol 25(1):75–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schömig A, von Beckerath N, Kastrati A (2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 121(4):512–518

    Article  CAS  PubMed  Google Scholar 

  44. Baldwin RM, Ohlsson S, Pedersen RS, Mwinyi J, Ingelman-Sundberg M, Eliasson E, Bertilsson L (2008) Increased omeprazole metabolism in carriers of the CYP2C19*17 allele: a pharmacokinetic study in healthy volunteers. Br J Clin Pharmacol 65:767–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ohlsson Rosenborg S, Mwinyi J, Andersson M, Baldwin RM, Pedersen RS, Sim SC, Bertilsson L, Ingelman-Sundberg M, Eliasson E (2008) Kinetics of omeprazole and escitalopram in relation to the CYP2C19*17 allele in healthy subjects. Eur J Clin Pharmacol 64(12):1175–1179

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Industry and Innovation Department of the Gobierno of Aragon (Spain) (B14) with the participation of the European Social Fund.

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Zaragoza, 50009, Saragossa, Spain

    Jorge Vicente, Antonia Soriano, Ana Fanlo & Blanca Sinués

  2. Faculty of Medical Sciences, Central University of Ecuador, Sodiro N14-121 e Iquique, 170136, Quito, Ecuador

    Fabricio González-Andrade

  3. Department of Legal Medicine, University of Zaragoza, 50009, Saragossa, Spain

    Begoña Martínez-Jarreta

Authors
  1. Jorge Vicente
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Fabricio González-Andrade
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Antonia Soriano
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Ana Fanlo
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Begoña Martínez-Jarreta
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Blanca Sinués
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Jorge Vicente.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vicente, J., González-Andrade, F., Soriano, A. et al. Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study. Mol Biol Rep 41, 1267–1272 (2014). https://doi.org/10.1007/s11033-013-2971-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-013-2971-y

Keywords

Profiles

  1. Jorge Vicente View author profile
  2. Fabricio González-Andrade View author profile