ArticleDrug metabolism and disposition: the biological fate of chemicals2010
Hepatocyte nuclear factor 4{alpha} regulates rifampicin-mediated induction of CYP2C genes in primary cultures of human hepatocytes.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 33 citations in OpenAlex.
- A Transcriptional Regulatory Network Containing Nuclear Receptors and Long Noncoding RNAs Controls Basal and Drug-Induced Expression of Cytochrome P450s in HepaRG Cells.Molecular pharmacology · 2018Article
- The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo.Drug design, development and therapy · 2018Review
- CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver.Molecular pharmacology · 2016Article
- Up-Regulation of CYP2C19 Expression by BuChang NaoXinTong via PXR Activation in HepG2 Cells.PloS one · 2016Article
- Cofunctional Subpathways Were Regulated by Transcription Factor with Common Motif, Common Family, or Common Tissue.BioMed research international · 2015Article
- Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8.Frontiers in pharmacology · 2015Article
- Genome-wide discovery of drug-dependent human liver regulatory elements.PLoS genetics · 2014Article
- RBCK1, an E3 ubiquitin ligase, interacts with and ubiquinates the human pregnane X receptor.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- Article
- Human CYP2C8 is post-transcriptionally regulated by microRNAs 103 and 107 in human liver.Molecular pharmacology · 2012Article
- Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters.Biochemical pharmacology · 2012Review
- PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19.Pharmacogenetics and genomics · 2012Article
- Molecular mechanisms of genetic variation and transcriptional regulation of CYP2C19.Frontiers in genetics · 2012Article
- Med25 is required for RNA polymerase II recruitment to specific promoters, thus regulating xenobiotic and lipid metabolism in human liver.Molecular and cellular biology · 2011Article
- Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR.Advanced drug delivery reviews · 2010Review
- CCAAT/enhancer-binding protein alpha (C/EBPalpha) and hepatocyte nuclear factor 4alpha (HNF4alpha) synergistically cooperate with constitutive androstane receptor to transactivate the human cytochrome P450 2B6 (CYP2B6) gene: application to the development of a metabolically competent human hepatic cell model.The Journal of biological chemistry · 2010Article
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6 authors at 2 institutions in 1 country.
Funding
Abstract
CYP2C enzymes are expressed constitutively and comprise approximately 20% of the total cytochrome P450 in human liver. However, the factors influencing the transcriptional regulation of the CYP2C subfamily have only been addressed recently. In the present study, we used primary cultures of human hepatocytes to investigate the role of HNF4alpha in the pregnane X receptor (PXR)/rifampicin-mediated up-regulation of CYP2C8, CYP2C9, and CYP2C19 gene expression. We first identified new proximal cis-acting HNF4alpha sites in the proximal CYP2C8 promoter [at -181 base pairs (bp) from the translation start site] and the CYP2C9 promoter (at -211 bp). Both sites bound HNF4alpha in gel shift assays. Thus, these and recent studies identified a total of three HNF4alpha sites in the CYP2C9 promoter and two in the CYP2C8 promoter. Mutational studies showed that the HNF4alpha sites are needed for up-regulation of the CYP2C8 and CYP2C9 promoters by rifampicin. Furthermore, silencing of HNF4alpha abolished transactivation of the CYP2C8 and CYP2C9 promoters by rifampicin. Constitutive promoter activity was also decreased. Quantitative polymerase chain reaction analysis demonstrated that silencing HNF4alpha reduced the constitutive expression of CYP2C8 (53%), CYP2C9 (55%), and CYP2C19 (43%) mRNAs and significantly decreased the magnitude of the rifampicin-mediated induction of CYP2C8 (6.6- versus 2.7-fold), CYP2C9 (3- versus 1.5-fold), and CYP2C19 (1.8- versus 1.1-fold). These results provide clear evidence that HNF4alpha contributes to the constitutive expression of the human CYP2C genes and is also important for up-regulation by the PXR agonist rifampicin.
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