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Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism

The Pharmacogenomics Journal volume 8, pages 268–277 (2008)Cite this article

Abstract

Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype–genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6α-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c.521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0–∞). Functional studies suggested −271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.

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Abbreviations

AUC(0–∞):

area under the plasma concentration-time curve from time 0 to infinity

CYP:

cytochrome P450

HPLC:

high performance liquid chromatography

PCR:

polymerase chain reaction

SNP:

single nucleotide polymorphism

References

  1. Enayetallah AE, French RA, Thibodeau MS, Grant DF . Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in human tissues. J Histochem Cytochem 2004; 52: 447–454.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Jaakkola T, Laitila J, Neuvonen PJ, Backman JT . Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 2006; 99: 44–51.

    Article  CAS  PubMed  Google Scholar 

  4. Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT . Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol 2005; 97: 249–256.

    Article  CAS  PubMed  Google Scholar 

  5. Niemi M, Tornio A, Pasanen MK, Fredrikson H, Neuvonen PJ, Backman JT . Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Eur J Clin Pharmacol 2006; 62: 463–472.

    Article  CAS  PubMed  Google Scholar 

  6. Lundblad MS, Stark K, Eliasson E, Oliw E, Rane A . Biosynthesis of epoxyeicosatrienoic acids varies between polymorphic CYP2C enzymes. Biochem Biophys Res Commun 2005; 327: 1052–1057.

    Article  CAS  PubMed  Google Scholar 

  7. Yasar U, Bennet AM, Eliasson E, Lundgren S, Wiman B, De Faire U et al. Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction. Pharmacogenetics 2003; 13: 715–720.

    Article  CAS  PubMed  Google Scholar 

  8. Bahadur N, Leathart JB, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R et al. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol 2002; 64: 1579–1589.

    Article  CAS  PubMed  Google Scholar 

  9. Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ . Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 2002; 30: 1352–1356.

    Article  PubMed  Google Scholar 

  10. Ishikawa C, Ozaki H, Nakajima T, Ishii T, Kanai S, Anjo S et al. A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin. J Hum Genet 2004; 49: 582–585.

    Article  PubMed  Google Scholar 

  11. Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ . Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002; 72: 685–691.

    Article  CAS  PubMed  Google Scholar 

  12. Cavaco I, Stromberg-Norklit J, Kaneko A, Msellem MI, Dahoma M, Ribeiro VL et al. CYP2C8 polymorphism frequencies among malaria patients in Zanzibar. Eur J Clin Pharmacol 2005; 61: 15–18.

    Article  CAS  PubMed  Google Scholar 

  13. Soyama A, Saito Y, Komamura K, Ueno K, Kamakura S, Ozawa S et al. Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift. Drug Metab Pharmacokinet 2002; 17: 374–377.

    Article  CAS  PubMed  Google Scholar 

  14. Weise A, Grundler S, Zaumsegel D, Klotzek M, Grondahl B, Forst T et al. Development and evaluation of a rapid and reliable method for cytochrome P450 2C8 genotyping. Clin Lab 2004; 50: 141–148.

    CAS  PubMed  Google Scholar 

  15. Rahman A, Korzekwa KR, Grogan J, Gonzalez FJ, Harris JW . Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 1994; 54: 5543–5546.

    CAS  PubMed  Google Scholar 

  16. Taniguchi R, Kumai T, Matsumoto N, Watanabe M, Kamio K, Suzuki S et al. Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4. J Pharmacol Sci 2005; 97: 83–90.

    Article  CAS  PubMed  Google Scholar 

  17. Ma B, Subramanian R, Schrag ML, Rodrigues AD, Tang C . Cytochrome P450 2C8 (CYP2C8)-mediated hydroxylation of an endothelin ETA receptor antagonist in human liver microsomes. Drug Metab Dispos 2004; 32: 473–478.

    Article  PubMed  Google Scholar 

  18. Walsky RL, Obach RS, Gaman EA, Gleeson JP, Proctor WR . Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Dispos 2005; 33: 413–418.

    Article  CAS  PubMed  Google Scholar 

  19. Ferguson SS, Chen Y, LeCluyse EL, Negishi M, Goldstein JA . Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Mol Pharmacol 2005; 68: 747–757.

    CAS  PubMed  Google Scholar 

  20. Niemi M, Leathart JB, Neuvonen M, Backman JT, Daly AK, Neuvonen PJ . Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide. Clin Pharmacol Ther 2003; 74: 380–387.

    Article  CAS  PubMed  Google Scholar 

  21. Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 2005; 77: 468–478.

    Article  CAS  PubMed  Google Scholar 

  22. Kirchheiner J, Thomas S, Bauer S, Tomalik-Scharte D, Hering U, Doroshyenko O et al. Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Clin Pharmacol Ther 2006; 80: 657–667.

    Article  CAS  PubMed  Google Scholar 

  23. Soyama A, Saito Y, Hanioka N, Murayama N, Nakajima O, Katori N et al. Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. Biol Pharm Bull 2001; 24: 1427–1430.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Westlind A, Lofberg L, Tindberg N, Andersson TB, Ingelman-Sundberg M . Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′-upstream regulatory region. Biochem Biophys Res Commun 1999; 259: 201–205.

    Article  CAS  PubMed  Google Scholar 

  26. Westlind-Johnsson A, Malmebo S, Johansson A, Otter C, Andersson TB, Johansson I et al. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos 2003; 31: 755–761.

    Article  CAS  PubMed  Google Scholar 

  27. Rodriguez-Antona C, Jande M, Rane A, Ingelman-Sundberg M . Identification and phenotype characterization of two CYP3A haplotypes causing different enzymatic capacity in fetal livers. Clin Pharmacol Ther 2005; 77: 259–270.

    Article  CAS  PubMed  Google Scholar 

  28. Consortium TIH . The International HapMap Project. Nature 2003; 426: 789–796.

    Article  Google Scholar 

  29. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  30. Stephens M, Scheet P . Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 2005; 76: 449–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ . Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46: 347–351.

    Article  CAS  PubMed  Google Scholar 

  33. Niemi M, Kajosaari LI, Neuvonen M, Backman JT, Neuvonen PJ . The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br J Clin Pharmacol 2004; 57: 441–447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kajosaari LI, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ . Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide. Br J Clin Pharmacol 2004; 58: 390–396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kajosaari LI, Niemi M, Neuvonen M, Laitila J, Neuvonen PJ, Backman JT . Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther 2005; 78: 388–399.

    Article  CAS  PubMed  Google Scholar 

  36. Kajosaari LI, Niemi M, Backman JT, Neuvonen PJ . Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin Pharmacol Ther 2006; 79: 231–242.

    Article  CAS  PubMed  Google Scholar 

  37. Kajosaari LI, Jaakkola T, Neuvonen PJ, Backman JT . Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide. Eur J Clin Pharmacol 2006; 62: 217–223.

    Article  CAS  PubMed  Google Scholar 

  38. Schreiber E, Matthias P, Muller MM, Schaffner W . Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic Acids Res 1989; 17: 6419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pitarque M, Rodriguez-Antona C, Oscarson M, Ingelman-Sundberg M . Transcriptional regulation of the human CYP2A6 gene. J Pharmacol Exp Ther 2005; 313: 814–822.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by grants from The Swedish Research Council, The Swedish Cancer Foundation, Cristina Rodríguez-Antona's Marie Curie Fellowships of the European Community contract numbers QLG5-CT-2002-51733 and MERG-CG-6-2005-014881, the ‘Ramon y Cajal’ programme from the Spanish Ministry of Education and Science, and the Sigrid Juselius Foundation (Helsinki, Finland).

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institute, Stockholm, Sweden

    C Rodríguez-Antona & M Ingelman-Sundberg

  2. Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Madrid, Spain

    C Rodríguez-Antona & M Robledo

  3. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    M Niemi, J T Backman, L I Kajosaari & P J Neuvonen

Authors
  1. C Rodríguez-Antona
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  2. M Niemi
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  4. L I Kajosaari
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Correspondence to C Rodríguez-Antona.

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None declared.

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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Rodríguez-Antona, C., Niemi, M., Backman, J. et al. Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism. Pharmacogenomics J 8, 268–277 (2008). https://doi.org/10.1038/sj.tpj.6500482

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