Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Drug Metabolism and Personalized Therapy

Official journal of the European Society of Pharmacogenomics and Personalised Therapy

Editor-in-Chief: Llerena, Adrián

Ed. by Benjeddou, Mongi

Editorial Board Member: Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario / Hubacek, Jaroslav A. / Ingelman-Sundberg, Magnus / Maitland-van der Zee, Anke-Hilse / Manolopoulos, Vangelis G. / Marc, Janja / Melichar, Bohuslav / Meyer, Urs A. / Nair, Sujit / Nofziger, Charity / Peiro, Ana / Sadee, Wolfgang / Salazar, Luis A. / Simmaco, Maurizio / Turpeinen, Miia / Schaik, Ron / Shin, Jae-Gook / Visvikis-Siest, Sophie / Zanger, Ulrich M.

4 Issues per year

CiteScore 2016: 1.40

SCImago Journal Rank (SJR) 2016: 0.413
Source Normalized Impact per Paper (SNIP) 2016: 0.537

See all formats and pricing
More options …
Volume 28, Issue 1 (Feb 2013)


Regulatory polymorphisms in CYP2C19 affecting hepatic expression

Jonathan C. Sanford
  • Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Yingying Guo
  • Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Wolfgang Sadee
  • Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Danxin Wang
  • Corresponding author
  • Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2013-02-14 | DOI: https://doi.org/10.1515/dmdi-2012-0038


Background: Cytochrome P450 2C19 is responsible for the metabolism of many drugs, including the activation of clopidogrel. The allele CYP2C19*17 is associated with ultra-rapid metabolizer phenotypes by increasing gene transcription. This study tests to what extent CYP2C19*17 enhances CYP2C19 expression in human liver and whether additional regulatory variants contribute to variation in CYP2C19 expression.

Methods: CYP2C19 mRNA was measured with quantitative real-time PCR (qRT-PCR), enzyme activity as metabolic velocity with S-mephenytoin as the substrate and allelic mRNA expression ratio with SNaPshot in human livers. CYP2C19 transcribed exons and a 4kb promoter region were sequenced using IonTorrent PGM or Sanger sequencing and screened for polymorphisms associated with total hepatic CYP2C19 mRNA, enzyme activity and allelic mRNA ratios.

Results: Livers heterozygote and homozygous for CYP2C19*17 had mRNA levels 1.8-fold (p=0.028) and 2.9-fold (p=0.006), respectively, above homozygous reference allele livers. CYP2C19*17 heterozygotes were also associated with increased allelic mRNA expression (allelic ratio ~1.8-fold, SD±0.6, p<0.005), whereas CYP2C19 enzyme activity was elevated 2.3-fold, with borderline significance (p=0.06) in CYP2C19*17 carriers. One liver sample of African ancestry displayed a 2-fold allelic expression ratio, and another sample, a ~12-fold increase in metabolic velocity. Neither case was accounted for by *17, which indicates the presence of additional regulatory variants.

Conclusions: Our findings confirm *17 as a regulatory polymorphism enhancing hepatic CYP2C19 expression 2-fold with potential to compensate for the loss of function allele CYP2C19*2. Additional regulatory factors may also enhance CYP2C19 expression in African American populations.

This article offers supplementary material which is provided at the end of the article.

Keywords: allelic expression imbalance; biomarker; clopidogrel; cytochrome P450; CYP2C19; polymorphism


  • 1.

    Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol 2008;21:70–83.Google Scholar

  • 2.

    Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010;38:92–9.Web of ScienceGoogle Scholar

  • 3.

    Karam WG, Goldstein JA, Lasker JM, Ghanayem BI. Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes. Drug Metab Dispos 1996;24:1081–7.Google Scholar

  • 4.

    Ohlsson Rosenborg S, Mwinyi J, Andersson M, Baldwin RM, Pedersen RS, Sim SC, et al. Kinetics of omeprazole and escitalopram in relation to the CYP2C19*17 allele in healthy subjects. Eur J Clin Pharmacol 2008;64:1175–9.Web of ScienceCrossrefGoogle Scholar

  • 5.

    The Human Cytochrome P450 (CYP) Allele Nomenclature Committee. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. CYP2C19 allele nomenclature. Available at: http://www.cypalleles.ki.se/cyp2c19.htm. Accessed on 15 October 2012.

  • 6.

    de Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994;46:594–8.Google Scholar

  • 7.

    de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994;269:15419–22.Google Scholar

  • 8.

    Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011;90:328–32.Web of ScienceGoogle Scholar

  • 9.

    The 1000 Genomes Project. 1000 Genomes Browser. Available at: http://browser.1000genomes.org. Accessed on 15 October 2012.Google Scholar

  • 10.

    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354–62.Google Scholar

  • 11.

    Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J Am Med Assoc 2009;302:849–57.Google Scholar

  • 12.

    Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. J Am Med Assoc 2010;304:1821–30.Web of ScienceGoogle Scholar

  • 13.

    Hwang SJ, Jeong YH, Kim IS, Koh JS, Kang MK, Park Y, et al. The cytochrome 2C19*2 and *3 alleles attenuate response to clopidogrel similarly in East Asian patients undergoing elective percutaneous coronary intervention. Thromb Res 2011;127:23–8.Web of ScienceGoogle Scholar

  • 14.

    U.S Food and Drug Administration. Information on clopidogrel bisulfate (marketed as Plavix). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm190836.htm. Accessed on 17 September 2012.

  • 15.

    Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006;79:103–13.Google Scholar

  • 16.

    Tiroch KA, Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schomig A, et al. Protective effect of the CYP2C19*17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J 2010;160:506–12.Google Scholar

  • 17.

    Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010;121:512–8.Web of ScienceGoogle Scholar

  • 18.

    Pare G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010;363:1704–14.Google Scholar

  • 19.

    Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010;8:1685–93.Web of ScienceCrossrefGoogle Scholar

  • 20.

    Baldwin RM, Ohlsson S, Pedersen RS, Mwinyi J, Ingelman-Sundberg M, Eliasson E, et al. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br J Clin Pharmaco 2008;65:767–74.CrossrefWeb of ScienceGoogle Scholar

  • 21.

    Dolton MJ, McLachlan AJ. Clinical importance of the CYP2C19*17 variant allele for voriconazole. Br J Clin Pharmaco 2011;71:137–8.Web of ScienceCrossrefGoogle Scholar

  • 22.

    de Vos A, van der Weide J, Loovers HM. Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and clomipramine in Dutch hospitalized patients. Pharmacogenomics J 2011;11:359–67.Web of ScienceCrossrefGoogle Scholar

  • 23.

    Wang G, Lei HP, Li Z, Tan ZR, Guo D, Fan L, et al. The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol 2009;65:281–5.Web of ScienceCrossrefPubMedGoogle Scholar

  • 24.

    Goldstein JA, Faletto MB, Romkes-Sparks M, Sullivan T, Kitareewan S, Raucy JL, et al. Evidence that CYP2C19 is the major (S)-mephenytoin 4’-hydroxylase in humans. Biochemistry 1994;33:1743–52.CrossrefGoogle Scholar

  • 25.

    Gawronska-Szklarz B, Adamiak-Giera U, Wyska E, Kurzawski M, Gornik W, Kaldonska M, et al. CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers. Eur J Clin Pharmacol 2012;68:1267–74.CrossrefGoogle Scholar

  • 26.

    Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. Br Med J 2011;343:d4588.Web of ScienceGoogle Scholar

  • 27.

    Li Y, Tang HL, Hu YF, Xie HG. The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients. J Thromb Haemost 2012;10:199–206.CrossrefWeb of ScienceGoogle Scholar

  • 28.

    Jang JS, Cho KI, Jin HY, Seo JS, Yang TH, Kim DK, et al. Meta-analysis of cytochrome P450 2C19 polymorphism and risk of adverse clinical outcomes among coronary artery disease patients of different ethnic groups treated with clopidogrel. Am J Cardiol 2012;110:502–8.Web of ScienceGoogle Scholar

  • 29.

    Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J. Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmaco 2010;69:222–30.Google Scholar

  • 30.

    Satyanarayana Chakradhara Rao U, Devendran A, Satyamoorthy K, Shewade DG, Krishnamoorthy R, Chandrasekaran A. Functional characterization of promoter region polymorphisms of human CYP2C19 gene. Mol Biol Rep 2011;38:4171–9.Google Scholar

  • 31.

    Fukushima-Uesaka H, Saito Y, Maekawa K, Ozawa S, Hasegawa R, Kajio H, et al. Genetic variations and haplotypes of CYP2C19 in a Japanese population. Drug Metab Pharmacok 2005;20:300–7.CrossrefGoogle Scholar

  • 32.

    Pedersen RS, Brasch-Andersen C, Sim SC, Bergmann TK, Halling J, Petersen MS, et al. Linkage disequilibrium between the CYP2C19*17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations. Eur J Clin Pharmacol 2010;66:1199–205.Web of ScienceCrossrefGoogle Scholar

  • 33.

    Lim JE, Pinsonneault J, Sadee W, Saffen D. Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Mol Psychiatr 2007;12:491–501.Web of ScienceGoogle Scholar

  • 34.

    van der Hoeven TA, Coon MJ. Preparation and properties of partially purified cytochrome P-450 and reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase from rabbit liver microsomes. J Biol Chem 1974;249:6302–10.Google Scholar

  • 35.

    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–75.Google Scholar

  • 36.

    Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011;11:274–86.CrossrefWeb of ScienceGoogle Scholar

  • 37.

    Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genom 2005;15:693–704.Google Scholar

  • 38.

    Pinsonneault J, Nielsen CU, Sadee W. Genetic variants of the human H+/dipeptide transporter PEPT2: analysis of haplotype functions. J Pharmacol Exp Ther 2004;311:1088–96.Google Scholar

  • 39.

    Blaisdell J, Mohrenweiser H, Jackson J, Ferguson S, Coulter S, Chanas B, et al. Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenet Genom 2002;12:703–11.Google Scholar

  • 40.

    Barber RD, Harmer DW, Coleman RA, Clark BJ. GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues. Physiol Genomics 2005;21:389–95.CrossrefGoogle Scholar

  • 41.

    Baker JA, Weber J, Felke E, Price R, Hall SD, Hillgren K, et al. Characterization of a human liver bank as a tool for research in pharmacogenetics (PGx). Clin Pharmacol Ther 2011;89(Supp1):S75.Google Scholar

  • 42.

    Mwinyi J, Hofmann Y, Pedersen RS, Nekvindova J, Cavaco I, Mkrtchian S, et al. The transcription factor GATA-4 regulates cytochrome P4502C19 gene expression. Life Sci 2010; 86:699–706.Web of ScienceGoogle Scholar

  • 43.

    Chen Y, Ferguson SS, Negishi M, Goldstein JA. Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter. Mol Pharmacol 2003;64:316–24.CrossrefGoogle Scholar

  • 44.

    Furukawa M, Nishimura M, Ogino D, Chiba R, Ikai I, Ueda N, et al. Cytochrome p450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver. Cancer Sci 2004;95:520–9.Google Scholar

About the article

Corresponding author: Danxin Wang, Program in Pharmacogenomics, Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5178 Graves Hall, Columbus, OH 43210, USA, Phone: +1 614 292-7336, Fax: +1 614 292-7232

Received: 2012-10-23

Accepted: 2013-01-03

Published Online: 2013-02-14

Published in Print: 2013-02-01

Citation Information: Drug Metabolism and Drug Interactions, ISSN (Online) 2191-0162, ISSN (Print) 0792-5077, DOI: https://doi.org/10.1515/dmdi-2012-0038.

Export Citation

©2013 by Walter de Gruyter Berlin Boston. Copyright Clearance Center

Supplementary Article Materials

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Kathryn Elisa Burns, Phillip Shepherd, Graeme Finlay, Malcolm Drummond Tingle, and Nuala Ann Helsby
Xenobiotica, 2017, Page 1
Robin P. Smith, Walter L. Eckalbar, Kari M. Morrissey, Marcelo R. Luizon, Thomas J. Hoffmann, Xuefeng Sun, Stacy L. Jones, Shelley Force Aldred, Anuradha Ramamoorthy, Zeruesenay Desta, Yunlong Liu, Todd C. Skaar, Nathan D. Trinklein, Kathleen M. Giacomini, Nadav Ahituv, and Anna Di Rienzo
PLoS Genetics, 2014, Volume 10, Number 10, Page e1004648
K. E. Burns, W.-Y. Lo, M. P. Findlay, K. Sharples, G. Laking, and N. A. Helsby
Cancer Chemotherapy and Pharmacology, 2016, Volume 77, Number 1, Page 195
Y Shirasaka, A S Chaudhry, M McDonald, B Prasad, T Wong, J C Calamia, A Fohner, T A Thornton, N Isoherranen, J D Unadkat, A E Rettie, E G Schuetz, and K E Thummel
The Pharmacogenomics Journal, 2016, Volume 16, Number 4, Page 375
A Ortega-Vázquez, P Dorado, I Fricke-Galindo, H Jung-Cook, N Monroy-Jaramillo, I E Martínez-Juárez, I Familiar-López, E Peñas-Lledó, A LLerena, and M López-López
The Pharmacogenomics Journal, 2016, Volume 16, Number 3, Page 286
Aydan Ozkaynakci, Medine Idrizoglu Gulcebi, Deniz Ergeç, Korkut Ulucan, Mustafa Uzan, Cigdem Ozkara, Ilter Guney, and Filiz Yilmaz Onat
Neurological Sciences, 2015, Volume 36, Number 3, Page 397

Comments (0)

Please log in or register to comment.
Log in