title: Med25 is required for estrogen receptor alpha (ERα)-mediated regulation of human CYP2C9 expression.
abstract: The CYP2C subfamily of cytochrome P450 enzymes is an important class of drug metabolizing enzymes in human liver. CYP2C9 is the most abundant member of the human CYP2C subfamily in liver and metabolizes ~15% of the therapeutic drugs as well as other xenobiotics and endogenous compounds. A number of nuclear receptors including xenobiotic-sensing receptors such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR) as well as liver enriched receptors hepatic nuclear factor 4α (HNF4α) and the estrogen receptor α (ERα) regulate CYP2C9 expression. Here, we show that Med25, a variable component of Mediator complex, enhanced ligand dependent ERα-mediated transcriptional activation of CYP2C9 promoter and interacts with activated ERα by 17β-estradiol through its C-terminal LXXLL motif. In conclusion, Med25 is identified as a new coactivator of ERα that is required for ERα-mediated regulation of CYP2C9 expression.
authors: Department of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China.
authors: Zhe
authors: Z
authors: Shi
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China.
authors: Wenjun
authors: W
authors: Yang
authors: Human Metabolism Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors: Joyce A
authors: JA
authors: Goldstein
authors: Department of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China. Electronic address: shuyunzh@gmail.com.
authors: Shu-Yun
authors: SY
authors: Zhang
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D065729:Cytochrome P-450 CYP2C9; D047628:Estrogen Receptor alpha / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D056892:Mediator Complex / Q000502:physiology*; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D047628:Estrogen Receptor alpha; C483045:MED25 protein, human; D056892:Mediator Complex; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases
keywords: CYP2C9; ERα; Med25; Transcription regulation