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Regulation of CYP2C19 Expression by Estrogen Receptor alpha: Implications for Estrogen-Dependent Inhibition of Drug Metabolism

2010-11Journal article Restricted access
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dc.contributor.authorMwinyi, Jessica
dc.contributor.authorCavaco, Isa
dc.contributor.authorPedersen, Rasmus Steen
dc.contributor.authorPersson, Anna
dc.contributor.authorBurkhardt, Sabrina
dc.contributor.authorMkrtchian, Souren
dc.contributor.authorIngelman-Sundberg, Magnus
dc.date.accessioned2018-12-07T14:57:59Z
dc.date.available2018-12-07T14:57:59Z
dc.date.issued2010-11
dc.description.abstractCytochrome P4502C19 (CYP2C19) is an important drug-metabolizing enzyme involved in the biotransformation of, for example, proton pump inhibitors and antidepressants. Several in vivo studies have shown that the CYP2C19 activity is inhibited by oral contraceptives, which can cause important drug interactions. The underlying molecular mechanism has been suggested to be competitive inhibition. However, the results presented here indicate that estradiol derivatives down-regulate CYP2C19 expression via estrogen receptor (ER)alpha, which interacts with the newly identified ER-binding half site [estrogen response element (ERE)] at the position -151/-147 in the CYP2C19 promoter. In gene reporter experiments in Huh-7 hepatoma cells, the activity of the luciferase construct carrying a 1.6-kb long CYP2C19 promoter fragment cotransfected with ER alpha was down-regulated upon treatment with 17 beta-estradiol (EE) or 17 alpha-ethinylestradiol (ETE) at half-maximum concentrations of 10(-7) and 10(-8) M, respectively. Mutations introduced into the ERE half site -151/-147 significantly inhibited these ligand-dependent effects. Electrophoretic mobility shift assays and quantitative chromatin immunoprecipitation experiments revealed that estrogen receptor alpha binds to this element. A significant suppression of CYP2C19 transcription by female sex steroids was confirmed by reverse transcription polymerase chain reaction after hormonal treatment of human hepatocytes. Inhibition experiments using a stable human embryonic kidney 293 CYP2C19 cell line revealed competitive inhibition at much higher concentrations of EE and ETE compared with those required for transcriptional inhibition. These results indicate that both EE and ETE inhibit CYP2C19 expression via an ER alpha-dependent regulatory pathway, thus providing a new insight into the molecular mechanism behind the inhibitory effect of oral contraceptives on CYP2C19 activity.
dc.description.sponsorshipHjarnfonden, Torsten och Ragnar Soderbergs Stiftelser [MT22/08]; Swedish Research Council [K2008-66X05949-28-3]; Danish Agency of Science, Technology and Innovation; Lundbeck Foundation; Portuguese Foundation for Science and Technology [SFRH/BPD/34152/2006]
dc.identifier.doi10.1124/mol.110.065540
dc.identifier.issn0026-895X
dc.identifier.urihttp://hdl.handle.net/10400.1/11801
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics
dc.relation.publisherversionhttp://molpharm.aspetjournals.org/content/molpharm/early/2010/07/30/mol.110.065540.full.pdf
dc.subjectOral-contraceptives
dc.subjectHealthy-volunteers
dc.subjectSignaling pathways
dc.subjectHuman liver
dc.subjectFemale sex
dc.subjectEr-beta
dc.subjectProtein
dc.subjectCyp2D6
dc.subjectGene
dc.subjectEthinylestradiol
dc.titleRegulation of CYP2C19 Expression by Estrogen Receptor alpha: Implications for Estrogen-Dependent Inhibition of Drug Metabolism
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage894
oaire.citation.issue5
oaire.citation.startPage886
oaire.citation.titleMolecular Pharmacology
oaire.citation.volume78
person.familyNameLopes Neve Cavaco
person.givenNameIsa da Conceição
person.identifier.orcid0000-0002-8629-7129
person.identifier.scopus-author-id6602806914
rcaap.rightsrestrictedAccess
rcaap.typearticle
relation.isAuthorOfPublication621412af-f03a-4940-bd7e-2bada5f7cfc8
relation.isAuthorOfPublication.latestForDiscovery621412af-f03a-4940-bd7e-2bada5f7cfc8

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