Skip to main content

Advertisement

SpringerLink
Log in

CYP2D6 genotype and phenotype determination in a Mexican Mestizo population

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

Abstract

Objective

Although CYP2D6 genetic polymorphism plays an important role in interindividual and interethnic variability in drug response, very few pharmacogenetic data are available from Hispanic populations, including Mexicans. For this purpose, this study was undertaken to determine CYP2D6 genotype and phenotype in a healthy Mexican Mestizo population.

Methods

Genotyping of five CYP2D6 mutant alleles by PCR–RFLP, and CYP2D6*5 and duplicated CYP2D6 alleles by long-PCR was performed in two hundred and forty three Mexican Mestizos. Of these, one hundred subjects were also phenotyped using dextromethorphan as the probe drug.

Results

The frequency of CYP2D6*2, *3, *4, *5, *10, *17 was 19.34%, 1.44%, 11.21%, 2.67%, 12.45%, and 1.65%, respectively, while duplicated CYP2D6 alleles were found in 12.76% of the 243 genotyped subjects. Among the 100 phenotyped subjects, we identified ten (10%, 95% confidence interval of 4.12–15.9) individuals as poor metabolizers by using the published antimode for Caucasians. The mean log10 dextromethorphan/dextrorphan ratio of the total sample was −2.05. The mean (SD) of the log10 MR in the CYP2D6 subgroups was UM=−2.6 (0.86); EM=−2.09 (0.98); IM=−1.71 (1.06); and PM=0.42 (0.625). These data show a trend toward a smaller mean log MR (higher enzyme activity) as the number of active alleles increases.

Conclusions

The PM frequency of CYP2D6 in the population studied was 10%, which is very similar to Spanish Caucasians. The observed frequency of the CYP2D6 alleles tested was unique for the Mexican Mestizo sample analyzed, and in accordance to the Caucasian, Asian and African admixture in this population.

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
Fig. 2

Similar content being viewed by others

References

  1. Ingelman–Sundberg M (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5:6–13

    Article  PubMed  CAS  Google Scholar 

  2. Heim MH, Meyer UA (1992) Evolution of a highly polymorphic human cytochrome P450 cluster: CYP2D6. Genomics 14:49–58

    Article  PubMed  CAS  Google Scholar 

  3. Sundberg–Ingelman M, Daly AK, Nebert DW, eds. CYP allele nomenclature home page. http://www.ki.se/CYPalleles/cyp2d6.htm

  4. Meyer UA (1994) Pharmacogenetics: the slow, the rapid and the ultrarapid. Proc Natl Acad Sci USA 91:1983–1984

    Article  PubMed  CAS  Google Scholar 

  5. Zanger UM, Fischer J, Raimundo S, Stuven T, Evert BO, Schwab M, Eichelbaum M (2001) Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics 11:573–585

    Article  PubMed  CAS  Google Scholar 

  6. Llerena AL, Herraiz AG, Cobaleda J, Johansson I, Dahl ML (1993) Debrisoquine and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents. Clin Pharmacol Ther 54:606–611

    Article  PubMed  CAS  Google Scholar 

  7. Grasmäder K, Verwohlt PL, Rietschel M, Dragicevic A, Müller M, Hiemke C, Freymann N, Zobel A, Maier W, Rao ML (2004) Impact of polymorphisms of cytochrome–P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol 60:329–336

    PubMed  Google Scholar 

  8. Sachse C, Brockmoller J, Bauer S, Roots I (1997) Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295

    PubMed  CAS  Google Scholar 

  9. Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, Wilkinson GR, Branch RA (1985) Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 38:402–408

    Article  PubMed  CAS  Google Scholar 

  10. Masimirembwa C, Hasler JA (1997) Genetic polymorphism of drug metabolising enzymes in African populations: implications for the use of neuroleptics and antidepressants. Brain Res Bull 44:561–571

    Article  PubMed  CAS  Google Scholar 

  11. Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Morike K, Stuven T, Eichelbaum M (1998) Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 8:15–26

    Article  PubMed  CAS  Google Scholar 

  12. Bradford LD (2002) CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3:229–243

    Article  PubMed  CAS  Google Scholar 

  13. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 265:17209–17214

    PubMed  CAS  Google Scholar 

  14. Nakamura K, Ariyoshi N, Yokoi T, Ohgiya S, Chida M, Nagashima K, Inoue K, Kodama T, Shimada N, Kamataki T (2002) CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability. Biochem Biophys Res Commun 293:969–973

    Article  PubMed  CAS  Google Scholar 

  15. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman–Sundberg M (1994) Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 46:452–459

    PubMed  CAS  Google Scholar 

  16. Nishida Y, Fukuda T, Yamamoto I, Azuma J (2000) CYP2D6 genotypes in a Japanese population: low frequencies of CYP2D6 gene duplication but high frequency of CYP2D6*10. Pharmacogenetics 6:567–570

    Article  Google Scholar 

  17. Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang T–Y, Liao XM, Wang KY, Reviriego J, Iselius L, Sjövist F (1992) Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S–mephenytoin. Clin Pharmacol Ther 51:338–397

    Article  Google Scholar 

  18. Masimirembwa C, Persson I, Bertilsson L, Hasler J, Ingelman–Sundberg MA (1996) A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity. Br J Clin Pharmacol 42:713–719

    Article  PubMed  CAS  Google Scholar 

  19. Johansson I, Lundqvist E, Bertilsson L, Dahl ML, Sjoqvist F, Ingelman–Sundberg M (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11825–11829

    Article  PubMed  CAS  Google Scholar 

  20. Dahl ML, Johansson I, Bertilsson L, Ingelman–Sundberg M, Sjoqvist F (1995) Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 274:516–520

    PubMed  CAS  Google Scholar 

  21. Agúndez JA, Ledesma MC, Ladero JM, Benítez J (1995) Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin Pharm Ther 57:265–269

    Article  Google Scholar 

  22. 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 9:657–660

    Article  PubMed  CAS  Google Scholar 

  23. Scordo MG, Spina E, Facciola G, Avenoso A, Johansson I, Dahl ML (1999) Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9–hydroxyrisperidone. Psychopharmacology (Berl)147:300–305

    Article  CAS  Google Scholar 

  24. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman–Sundberg M (1996) Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 278:441–446

    PubMed  CAS  Google Scholar 

  25. McLellan RA, Oscarson M, Seidegard J, Evans DA, Ingelman–Sundberg M (1997) Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 7:187–191

    Article  PubMed  CAS  Google Scholar 

  26. Schur BC, Bjerke J, Nuwayhid N, Wong SH (2001) Genotyping of cytochrome P450 2D6*3 and *4 mutations using conventional PCR. Clin Chim Acta 308:25–31

    Article  PubMed  CAS  Google Scholar 

  27. Mendoza R, Wan YJ, Poland RE, Smith M, Zheng Y, Berman N, Lin KM (2001) CYP2D6 polymorphism in a Mexican American population. Clin Pharmacol Ther 70:552–560

    PubMed  CAS  Google Scholar 

  28. Hersberger M, Marti–Jaun J, Rentsch K, Hänseler E (2000) Rapid detection of the CYP2D6*3, CYP2D6*4, and CYP2D6*6 alleles by tetra–primer PCR and of the CYP2D6*5 allele by multiplex long PCR. Clin Chem 46:1072–1077

    PubMed  CAS  Google Scholar 

  29. Lovlie R, Daly AK, Molven A, Idle JR, Steen VM (1996) Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene. FEBS Lett 392:30–34

    Article  PubMed  CAS  Google Scholar 

  30. Ducharme J, Abdullah S, Wainer IW (1996) Dextromethorphan as an in vivo probe for the simultaneous determination of CYP2D6 and CYP3A activity. J Chromatogr B Biomed Appl 678:113–128

    Article  PubMed  CAS  Google Scholar 

  31. Schmid B, Bircher J, Preisig R, Kupfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation of oxidative O–demethylation with debrisoquine hydroxylation. Clin Pharmacol Ther 38:618–624

    Article  PubMed  CAS  Google Scholar 

  32. Benítez J, Llerena A, Cobaleda J (1988) Debrisoquin oxidation polymorphism in a Spanish population. Clin Pharmacol Ther 44:74–77

    Article  PubMed  Google Scholar 

  33. Henthorn TK, Benitez J, Avram MJ, Martinez C, Llerena A, Cobaleda J, Krejcie TC, Gibbons RD (1989) Assessment of the debrisoquin and dextromethorphan phenotyping tests by gaussian mixture distributions analysis. Clin Pharmacol Ther 45:328–333

    Article  PubMed  CAS  Google Scholar 

  34. Isaza CA, Henao J, Lopez AM, Cacabelos R (2000) Isolation, sequence and genotyping of the drug metabolizer CYP2D6 gene in the Colombian population. Methods Find Exp Clin Pharmacol 22:695–705

    Article  PubMed  CAS  Google Scholar 

  35. Jorge LF, Eichelbaum M, Griese EU, Inaba T, Arias TD (1999) Comparative evolutionary pharmacogenetics of CYP2D6 in Ngawbe and Embera Amerindians of Panama and Colombia: role of selection versus drift in world populations. Pharmacogenetics 9:217–228

    PubMed  CAS  Google Scholar 

  36. Agúndez JAG, Martínez C, Ledesma MC, LaDonda MG, Ladero Jm, Benítez J (1994) Clin Pharmacol Ther 55:412–417

    Article  PubMed  Google Scholar 

  37. Griese EU, Asante–Poku S, Ofori–Adjei D, Mikus G, Eichelbaum M (1999) Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population. Pharmacogenetics 9:715–723

    Article  PubMed  CAS  Google Scholar 

  38. Cerda–Flores RM, Budowle B, Jin L, Barton SA, Deka R, Chakraborty R (2002) Maximum likelihood estimates of admixture in Northeastern Mexico using 13 short tandem repeat loci. Am J Hum Biol 14:429–439

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a grant (37103–M) from Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico.

Author information

Authors and Affiliations

  1. Department of Biological Systems, Metropolitan Autonomous University– Xochimilco Campus, Calzada del Hueso 1100, Col. Villa Quietud, Coyoacán, 04960, Mexico City, Mexico

    Marisol López

  2. Department of Genetics and Molecular Biology, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez, Avenida Insurgentes Sur 3877, Col. La Fama, Tlalpan, 14269, Mexico City, Mexico

    Jorge Guerrero & María Elisa Alonso

  3. Department of Neuropsycopharmacology, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez, Avenida Insurgentes Sur 3877, Col. La Fama, Tlalpan, 14269, Mexico City, Mexico

    Helgi Jung–Cook

Authors
  1. Marisol López
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge Guerrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helgi Jung–Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. María Elisa Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marisol López.

Rights and permissions

Reprints and permissions

About this article

Cite this article

López, M., Guerrero, J., Jung–Cook, H. et al. CYP2D6 genotype and phenotype determination in a Mexican Mestizo population. Eur J Clin Pharmacol 61, 749–754 (2005). https://doi.org/10.1007/s00228-005-0038-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-005-0038-2

Keywords

Search

Navigation