Skip to main content
SpringerLink
Log in

CYP2C9 genetic variants and losartan oxidation in a Turkish population

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

Abstract

Objective

Cytochrome P 450 2C9 (CYP2C9) is a polymorphic enzyme catalysing the metabolism of several important drugs. Losartan has recently been suggested as a selective probe for CYP2C9 metabolic activity. The aim of the study was to determine the activity of CYP2C9, using losartan as a probe drug, in relation to CYP2C9 genotype in healthy Turkish subjects.

Methods

A single oral dose of 25 mg losartan was given to 85 Turkish unrelated subjects. Concentrations of losartan and its carboxylic acid metabolite, E3174, were analysed by means of high-performance liquid chromatography in urine collected for 8 h. The CYP2C9 genotypes were determined in 85 subjects using polymerase chain reaction-based endonuclease digestion methods specific for CYP2C9*2 and *3. Losartan oxidation was also studied in vitro, using human CYP2C8 and CYP2C9 enzymes expressed in yeast.

Results

The frequencies of the allelic variants CYP2C9*2 and CYP2C9*3 were 0.100 and 0.088, respectively. The urinary losartan/E3174 ratio was significantly higher in subjects with CYP2C9*1/*3 genotype (median 2.35, n=12) than in subjects with CYP2C9*1/*1 (0.71, n=58) and *1/*2 (0.85, n=10) genotypes (P<0.05). In contrast to CYP2C9, no E3174 was formed by CYP2C8 in vitro.

Conclusion

The urinary losartan to E3174 metabolic ratio after a 25-mg losartan dose was found to be a safe and useful phenotyping assay for CYP2C9 activity in vivo. CYP2C9*3 variant allele is a major determinant of the enzyme activity, and it decreases losartan metabolism significantly, while CYP2C9*2 allele has less impact on enzyme function.

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

References

  1. Aynacioglu AS, Brockmöller J, Bauer S, Sachse C, Güzelbey P, Öngen Z, Nacak M, Roots I (1999) Frequency of cytochrome P 450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48:409–415

    CAS  PubMed  Google Scholar 

  2. Brandolese R, Scordo MG, Spina E, Gusella M, Padrini R (2001) Severe phenytoin intoxication in a subject homozygous for CYP2C9*3. Clin Pharm Ther 70:391–394

    Article  CAS  Google Scholar 

  3. Caraco Y, Muszkat M, Wood AJ (2001) Phenytoin metabolic ratio: a putative marker of CYP2C9 activity in vivo. Pharmacogenetics 11:587–596

    Google Scholar 

  4. Christensen M, Andersson K, Dalen P, Mirghani RA, Muirhead GJ, Nordmark A, Tybring G, Wahlberg A, Yasar Ü, Bertilsson L (2003) The Karolinska cocktail for phenotyping of five human cytochrome P 450 enzymes. Clin Pharmacol Ther 73:517–528

    Article  CAS  PubMed  Google Scholar 

  5. Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, Goldstein JA (2001) Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 11:597–607

    Article  CAS  PubMed  Google Scholar 

  6. Daly AK, King BP (2003) Pharmacogenetics of oral anticoagulants. Pharmacogenetics 13:247–252

    Google Scholar 

  7. Dickmann LJ, Rettie AE, Kneller MB, Kim RB, Wood AJ, Stein CM, Wilkinson GR, Schwarz UI (2001) Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 60:382–387

    CAS  PubMed  Google Scholar 

  8. Gaedigk A, Casley WL, Tyndale RF, Sellers EM, Jurima-Romet M, Leeder JS (2001) Cytochrome P 450 2C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations. Can J Physiol Pharmacol 79:841–847

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Gotoh O (1992) Substrate recognition sites in cytochrome P 450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J Biol Chem 267:83–90

    CAS  PubMed  Google Scholar 

  11. Imai J, Ieiri I, Mamiya K, Miyahara S, Furuumi H, Nanba E, Yamane M, Fukumaki Y, Ninomiya H, Tashiro N, Otsubo K, Higuchi S (2000) Polymorphism of the cytochrome P 450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. Pharmacogenetics 10:85–89

    CAS  PubMed  Google Scholar 

  12. Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT (1999) Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 9:71–80

    CAS  PubMed  Google Scholar 

  13. Kidd RS, Curry TB, Gallagher S, Edeki T, Blaisdell J, Goldstein JA (2001) Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 11:803–808

    CAS  PubMed  Google Scholar 

  14. Kim JS, Nafziger AN, Gaedigk A, Dickmann LJ, Rettie AE, Bertino JS Jr (2001) Effects of oral vitamin K on S- and R-warfarin pharmacokinetics and pharmacodynamics: enhanced safety of warfarin as a CYP2C9 probe. J Clin Pharmacol 41:715–722

    Article  CAS  PubMed  Google Scholar 

  15. Lee CR, Goldstein JA, Pieper JA (2002) Cytochrome P 450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12:251–263

    Google Scholar 

  16. Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA (2003) Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Eur J Clin Pharmacol 58:791–794

    CAS  PubMed  Google Scholar 

  17. Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA (2003) Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol 43:84–91

    Article  CAS  PubMed  Google Scholar 

  18. Schwarz UI (2003) Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. Eur J Clin Invest 33[Suppl 2]:23–30

  19. Scordo G, Aklillu E, Yasar Ü, Dahl M-L, Spina E, Ingelman-Sundberg M (2001) Genetic polymorphism of cytochrome P 450 2C9 in a Caucasian and a Black-African population. Br J Clin Pharmacol 52:447–450

    CAS  PubMed  Google Scholar 

  20. Sekino K, Kubota T, Okada Y, Yamada Y, Yamamoto K, Horiuchi R, Kimura K, Iga T (2003) Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects. Eur J Clin Pharmacol 59:589–592

    Article  CAS  PubMed  Google Scholar 

  21. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA (1996) The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6:341–349

    CAS  PubMed  Google Scholar 

  22. Takahashi H, Wilkinson GR, Caraco Y, Muszkat M, Kim RB, Kashima T, Kimura S, Echizen H (2003) Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients. Clin Pharmacol Ther 73:253–263

    Article  CAS  PubMed  Google Scholar 

  23. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45:205–251

    CAS  PubMed  Google Scholar 

  24. Wang SL, Huang J, Lai MD, Tsai JJ (1995) Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 5:37–42

    CAS  PubMed  Google Scholar 

  25. Yasar Ü, 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

    CAS  PubMed  Google Scholar 

  26. Yasar Ü, Eliasson E, Forslund-Bergengren C, Tybring G, Gadd M, Sjöqvist F, Dahl M-L (2001) The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. Eur J Clin Pharmacol 57:729–735

    Article  CAS  PubMed  Google Scholar 

  27. Yasar Ü, Tybring G, Hidestrand M, Oscarson M, Ingelman-Sundberg M, Dahl ML, Eliasson E (2001) Role of CYP2C9 polymorphism in losartan oxidation. Drug Metab Dispos 29:1051–1056

    CAS  PubMed  Google Scholar 

  28. Yasar Ü, Aklillu E, Canaparo R, Sandberg M, Sayi J, Roh H-K, Wennerholm A (2002) Analysis of CYP2C9*5 in Caucasian, Oriental and Black-African populations. Eur J Clin Pharmacol 58:555–558

    Article  CAS  PubMed  Google Scholar 

  29. Yasar Ü, Dahl M-L, Christensen M, Eliasson E (2002) Intra-individual variability in urinary losartan oxidation ratio, an in vivo-marker of CYP2C9 activity. Br J Clin Pharmacol 54:183–185

    Article  CAS  PubMed  Google Scholar 

  30. Yasar Ü, Forslund C, Tybring G, Dorado P, Llerena A, Sjöqvist F, Eliasson E, Dahl M-L (2002) Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype. Clin Pharmacol Ther 71:89–98

    CAS  PubMed  Google Scholar 

  31. Yasar Ü, Lundgren S, Eliasson E, Bennet A, Wiman B, De Faire U, Rane A (2002) Linkage between the CYP2C8 and CYP2C9 genetic polymorphisms. Biochem Biophys Res Commun 299:25–28

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Scientific and Technical Research Council of Turkey (SBAG-COST B15 –2356), and Hacettepe University Scientific Research Unit (01.02.101.001). The authors thank Aysun Dincel for laboratory assistance. The study was conducted in accordance with the current regulations of Turkey and Sweden. None of the authors claim any conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Hacettepe University Faculty of Medicine, 06100 Sihhiye, Ankara, Turkey

    Melih O. Babaoglu, Umit Yasar, S. Oguz Kayaalp & Atila Bozkurt

  2. Department of Laboratory Medicine, Division of Clinical Pharmacology at Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden

    Mia Sandberg & Erik Eliasson

  3. Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden

    Marja-Liisa Dahl

Authors
  1. Melih O. Babaoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Umit Yasar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mia Sandberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erik Eliasson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marja-Liisa Dahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Oguz Kayaalp
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Atila Bozkurt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Melih O. Babaoglu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Babaoglu, M.O., Yasar, U., Sandberg, M. et al. CYP2C9 genetic variants and losartan oxidation in a Turkish population. Eur J Clin Pharmacol 60, 337–342 (2004). https://doi.org/10.1007/s00228-004-0785-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-004-0785-5

Keywords

Search

Navigation