Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response

Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response

Rolf P Kreutz,1,2 Janelle Owens,2 Yan Jin,2 Perry Nystrom,2 Zeruesenay Desta,2 Yvonne Kreutz,2 Jeffrey A Breall,1 Lang Li,3 ChienWei Chiang,3 Richard J Kovacs,1 David A Flockhart21Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, 3Center for...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Kreutz RP, Owens J, Jin Y, Nystrom P, Desta Z, Kreutz Y, Breall JA, Li L, Chiang CW, Kovacs RJ, Flockhart DA
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2013
Materias:
Therapeutics. Pharmacology
RM1-950
Acceso en línea:https://doaj.org/article/504c2469c1fe406db34ebc07c8e9cbf3
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:504c2469c1fe406db34ebc07c8e9cbf3
record_format dspace
spelling oai:doaj.org-article:504c2469c1fe406db34ebc07c8e9cbf32021-12-02T08:26:20ZCytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response1179-1438https://doaj.org/article/504c2469c1fe406db34ebc07c8e9cbf32013-12-01T00:00:00Zhttp://www.dovepress.com/cytochrome-p450-3a422-ppar-alpha-and-arnt-polymorphisms-and-clopidogre-a15225https://doaj.org/toc/1179-1438Rolf P Kreutz,1,2 Janelle Owens,2 Yan Jin,2 Perry Nystrom,2 Zeruesenay Desta,2 Yvonne Kreutz,2 Jeffrey A Breall,1 Lang Li,3 ChienWei Chiang,3 Richard J Kovacs,1 David A Flockhart21Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, 3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USAAbstract: Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 µM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.Keywords: clopidogrel, pharmacogenetics, CYP450, platelet aggregationKreutz RPOwens JJin YNystrom PDesta ZKreutz YBreall JALi LChiang CWKovacs RJFlockhart DADove Medical PressarticleTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol 2013, Iss Issue 1, Pp 185-192 (2013)
institution DOAJ
collection DOAJ
language EN
topic Therapeutics. Pharmacology
RM1-950
spellingShingle Therapeutics. Pharmacology
RM1-950
Kreutz RP
Owens J
Jin Y
Nystrom P
Desta Z
Kreutz Y
Breall JA
Li L
Chiang CW
Kovacs RJ
Flockhart DA
Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response
description Rolf P Kreutz,1,2 Janelle Owens,2 Yan Jin,2 Perry Nystrom,2 Zeruesenay Desta,2 Yvonne Kreutz,2 Jeffrey A Breall,1 Lang Li,3 ChienWei Chiang,3 Richard J Kovacs,1 David A Flockhart21Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, 3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USAAbstract: Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 µM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.Keywords: clopidogrel, pharmacogenetics, CYP450, platelet aggregation
format article
author Kreutz RP
Owens J
Jin Y
Nystrom P
Desta Z
Kreutz Y
Breall JA
Li L
Chiang CW
Kovacs RJ
Flockhart DA
author_facet Kreutz RP
Owens J
Jin Y
Nystrom P
Desta Z
Kreutz Y
Breall JA
Li L
Chiang CW
Kovacs RJ
Flockhart DA
author_sort Kreutz RP
title Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response
title_short Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response
title_full Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response
title_fullStr Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response
title_full_unstemmed Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response
title_sort cytochrome p450 3a4*22, ppar-α, and arnt polymorphisms and clopidogrel response
publisher Dove Medical Press
publishDate 2013
url https://doaj.org/article/504c2469c1fe406db34ebc07c8e9cbf3
work_keys_str_mv AT kreutzrp cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT owensj cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT jiny cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT nystromp cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT destaz cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT kreutzy cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT breallja cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT lil cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT chiangcw cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT kovacsrj cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
AT flockhartda cytochromep4503a422pparalphaandarntpolymorphismsandclopidogrelresponse
_version_ 1718398482349293568

Ejemplares similares