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Hepatocyte nuclear factors (HNF) 4α and 1α synergistically up‐regulate car‐mediated transcriptional activity of human CYP2C9 gene
Author(s) -
Xie H.G.,
Lee W.,
Yu C.,
Stein C.M.,
Kim R.B.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.089
Subject(s) - transactivation , transfection , luciferase , hepatocyte nuclear factors , pregnane x receptor , reporter gene , gene , hepatocyte nuclear factor 4 , biology , microbiology and biotechnology , chemistry , gene expression , transcription factor , genetics , nuclear receptor
Background There are two CAR response elements, −1783/−1856 bp and −2899/−2883 bp, in the −3kb CYP2C9 promoter region. The proximal element is thought to mediate PXR response while the distal one may have a CAR effect. HNFs are important co‐regulators of gene expression. The aim of this study was to define the roles of HNF4α and HNF1α in CAR‐mediated transactivation of human CYP2C9 gene. Methods and Results Three CYP2C9 ‐luciferase reporter constructs (−3kb, −2kb, −1kb) were transfected into HepG2 cells. Co‐transfection with CAR, HNF4α, and HNF1α alone did not significantly change their luciferase activities (LA). For the −3kb and −2kb constructs, compared with CAR alone, CAR co‐transfection with HNF4α increased LA 3.9‐ and 2.9‐fold ( P <0.001, and P <0.01), respectively. For the −1kb construct, no significant differences were observed when CAR alone or CAR was co‐transfected with HNF4α or HNF1α. Similarly, for the −2kb construct, HNF4α increased mouse CAR‐mediated LA 2.6‐fold ( P <0.05) but HNF1α had a smaller effect. Conclusions These data suggest that HNF4α, and to a lesser extent HNF1α, synergistically up‐regulate CAR‐mediated transcriptional activity of CYP2C9 gene, and that there is a CAR‐response element between −1kb and −2kb of CYP2C9 promoter region as previously noted. Clinical Pharmacology & Therapeutics (2005) 77 , P23–P23; doi: 10.1016/j.clpt.2004.11.089