Regulatory Polymorphisms in CYP2C19 Affecting Hepatic Expression

Overview

Journal Drug Metabol Drug Interact

Publisher De Gruyter

Date 2013 Feb 16

PMID 23412869

Citations 14

Authors

Jonathan C Sanford

Yingying Guo

Wolfgang Sadee

Danxin Wang

Affiliations

Soon will be listed here.

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.

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References

Barber R, Harmer D, Coleman R, Clark B . GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues. Physiol Genomics. 2005; 21(3):389-95. DOI: 10.1152/physiolgenomics.00025.2005. View

de Morais S, Wilkinson G, Blaisdell J, Nakamura K, Meyer U, Goldstein J . The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem. 1994; 269(22):15419-22. View

Jang J, Cho K, Jin H, Seo J, Yang T, Kim D . 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(4):502-8. DOI: 10.1016/j.amjcard.2012.04.020. View

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 Pharmacol. 2010; 69(3):222-30. PMC: 2829691. DOI: 10.1111/j.1365-2125.2009.03578.x. View

Mwinyi J, Hofmann Y, Pedersen R, Nekvindova J, Cavaco I, Mkrtchian S . The transcription factor GATA-4 regulates cytochrome P4502C19 gene expression. Life Sci. 2010; 86(19-20):699-706. DOI: 10.1016/j.lfs.2010.02.021. View

de Morais S, Wilkinson G, Blaisdell J, Meyer U, Nakamura K, Goldstein J . Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994; 46(4):594-8. View

Bauer T, Bouman H, van Werkum J, Ford N, Ten Berg J, Taubert D . Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ. 2011; 343:d4588. PMC: 3191560. DOI: 10.1136/bmj.d4588. View

Karam W, Goldstein J, Lasker J, Ghanayem B . Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes. Drug Metab Dispos. 1996; 24(10):1081-7. View

Tiroch K, Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schomig A . Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J. 2010; 160(3):506-12. DOI: 10.1016/j.ahj.2010.06.039. View

10.

Scott S, Sangkuhl K, Gardner E, Stein C, Hulot J, Johnson J . Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011; 90(2):328-32. PMC: 3234301. DOI: 10.1038/clpt.2011.132. View

11.

Fukushima-Uesaka H, Saito Y, Maekawa K, Ozawa S, Hasegawa R, Kajio H . Genetic variations and haplotypes of CYP2C19 in a Japanese population. Drug Metab Pharmacokinet. 2005; 20(4):300-7. DOI: 10.2133/dmpk.20.300. View

12.

Ohlsson Rosenborg S, Mwinyi J, Andersson M, Baldwin R, Pedersen R, Sim S . Kinetics of omeprazole and escitalopram in relation to the CYP2C19*17 allele in healthy subjects. Eur J Clin Pharmacol. 2008; 64(12):1175-9. DOI: 10.1007/s00228-008-0529-z. View

13.

Sim S, Risinger C, Dahl M, Aklillu E, Christensen M, Bertilsson L . 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(1):103-13. DOI: 10.1016/j.clpt.2005.10.002. View

14.

Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J . Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010; 121(4):512-8. DOI: 10.1161/CIRCULATIONAHA.109.885194. View

15.

Dolton M, McLachlan A . Clinical importance of the CYP2C19*17 variant allele for voriconazole. Br J Clin Pharmacol. 2010; 71(1):137-8. PMC: 3018036. DOI: 10.1111/j.1365-2125.2010.03801.x. View

16.

van der Hoeven T, Coon M . 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(19):6302-10. View

17.

Mega J, Close S, Wiviott S, Shen L, Hockett R, Brandt J . Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2008; 360(4):354-62. DOI: 10.1056/NEJMoa0809171. View

18.

Li Y, Tang H, Hu Y, Xie H . The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients. J Thromb Haemost. 2011; 10(2):199-206. DOI: 10.1111/j.1538-7836.2011.04570.x. View

19.

Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T . Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost. 2010; 8(8):1685-93. DOI: 10.1111/j.1538-7836.2010.03921.x. View

20.

Baldwin R, Ohlsson S, Pedersen R, Mwinyi J, Ingelman-Sundberg M, Eliasson E . Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br J Clin Pharmacol. 2008; 65(5):767-74. PMC: 2432489. DOI: 10.1111/j.1365-2125.2008.03104.x. View