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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.

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Volume 28, Issue 1 (Feb 2013)

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

Abstract

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

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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.

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