Upregulation of human CYP2C9 expression by Bisphenol A via estrogen receptor alpha (ERα) and Med25.
Bisphenol A (BPA) is an important industrial chemical, mainly used in the manufacture of polycarbonate plastic and epoxy resins. Due to its widespread use, humans have a high risk of exposure to BPA. BPA has been found to have adverse health effects such as interfering with hormone-related pathways and is well-known to act as an endocrine disruptor. The present study is the first to show the induction effect of BPA on gene expression and enzyme activity of CYP2C9, an important hepatic drug metabolizing enzyme in human. We further identify the mechanism of BPA upregulation of CYP2C9 expression. We show that BPA is able to transcriptionally activate CYP2C9 promoter through ERα and ERE site within the CYP2C9 promoter region in HepG2 cells, and can induce CYP2C9 gene expression and enzyme activity in human primary hepatocytes. Moreover, we demonstrate that Med25, a variable member of the Mediator complex, is a coactivator of ligand-activated ERα that interacts with ERα through its C-terminal LXXLL motif after BPA exposure, and is functionally involved in BPA-induced transcriptional regulation of CYP2C9 expression and enzyme activity. Our findings suggest that BPA exposure has a potential risk for adverse health effects in human liver metabolism by upregulation of CYP2C9 expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 970-978, 2017.
Department of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, PR China.
Jia-Yi
JY
Xu
Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, PR China.
Liang
L
Wu
Department of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, PR China.
Zhe
Z
Shi
Department of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, PR China.
Xiao-Jie
XJ
Zhang
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Neal A
NA
Englert
Department of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, PR China.
Shu-Yun
SY
Zhang
D001559:Benzhydryl Compounds / Q000009:adverse effects*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D052244:Endocrine Disruptors / Q000009:adverse effects*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D056892:Mediator Complex / Q000378:metabolism*; D008875:Middle Aged; D010636:Phenols / Q000009:adverse effects*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D065729:Cytochrome P-450 CYP2C9; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D056892:Mediator Complex; D010636:Phenols; C506487:ESR1 protein, human; C483045:MED25 protein, human; C450260:CYP2C9 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds
CYP2C9; ERα; Med25; bisphenol A; transcriptional regulation