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PIII‐26
Author(s) -
Xie H. G.,
Lee W.,
Stein C. M.,
Kim R. B.
Publication year - 2006
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.2005.12.234
Subject(s) - transactivation , luciferase , hepatocyte nuclear factor 4 , pregnane x receptor , transfection , chemistry , reporter gene , small heterodimer partner , microbiology and biotechnology , pharmacology , transcription factor , gene expression , biology , gene , nuclear receptor , biochemistry
BACKGROUND/AIMS Patients with HNF1α gene mutations exhibit marked hypersensitivity to hypoglycemic drugs (CYP2C9 substrates). Rif‐induced CYP2C9 gene expression is reduced by pretreatment with chenodeoxycholic acid, which induces expression of SHP‐1. SHP‐1 can repress HNF1α gene through the suppression of HNF4α and HNF4α synergistically activates PXR/Rif induction of CYP2C9 . This study examined the hypothesis that HNF1α activates Rif‐induced CYP2C9 transactivation and interacts with HNF4α and SHP‐1. METHODS CYP2C9 ‐luciferase reporter constructs (−3kb) were transfected into HepG2 cells, and PXR, HNF1α, HNF4α, SHP‐1 were co‐transfected individually or together. The cells were treated with or without Rif (10μM), followed by dual luciferase assays. Data are expressed as fold activation versus vector control. RESULTS Compared with PXR/Rif alone, cells co‐transfected with HNF1α or HNF4α significantly increased luciferase activity (3.6‐ and 4.6‐fold, P < .01), but those co‐transfected with both HNF1α and HNF4α only increased luciferase activity 4‐fold (P < .01). As expected, SHP‐1 significantly suppressed HNF4α‐mediated (13.9 ± 1.9 vs 2.6 ± 0.4, P < .05) and, to a lesser extent, HNF1α‐mediated (15.4± 1.9 vs 9.6 ± 1.6; P < .01) synergistic transactivation. CONCLUSIONS HNF1α and HNF4α individually up‐regulate rifampin induction of CYP2C9, but do not have additive or synergistic effects when expressed together. SHP‐1 suppresses HNF1α‐ and HNF4α‐ mediated PXR/rifampin induction of CYP2C9. Clinical Pharmacology & Therapeutics (2005) 79 , P65–P65; doi: 10.1016/j.clpt.2005.12.234