Abstract
The nuclear receptor constitutive active/androstane receptor (CAR) up-regulated expression of the apoptotic growth arrest and DNA-damage-inducible 45 β (GADD45B) gene in HepG2 cells. Overexpression of GADD45B augmented CAR-mediated induction of the human CYP2B gene by the CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and coactivated CAR-dependent transcription of the NR1-luciferase reporter gene. Small interfering RNA knockdown of GADD45B resulted in repression of both the induction and the coactivation. Induction of the mouse Cyp2b10 gene by TCPOBOP was profoundly attenuated in the primary hepatocytes prepared from GADD45B-knockout mice compared with those from wild-type mice. Because CAR is a key transcription factor that activates the genes that encode for xenobiotic metabolizing enzymes and transporters, GADD45B, acting as a CAR coactivator and coregulating CAR target genes, may be involved in hepatic drug metabolism and excretion of xenobiotics.
Footnotes
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This study was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.020628.
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ABBREVIATIONS: CAR, constitutive active/androstane receptor; RXR, retinoid X receptor; GADD45B, growth arrest and DNA-damage-inducible 45 β; MKK7, mitogen-activated protein kinase kinase 7; JNK, c-Jun NH2-terminal kinase; PB, phenobarbital; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; KO, knockout; PCR, polymerase chain reaction; siRNA, small interfering RNA; Luc, luciferase; DMSO, dimethyl sulfoxide; HCC, hepatocellular carcinoma; LPS, lipopolysaccharide.
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↵1 Current affiliation: Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
- Received January 25, 2008.
- Accepted March 21, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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