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SHORT COMMUNICATION

The Antiapoptotic Factor Growth Arrest and DNA-Damage-Inducible 45 β Regulates the Nuclear Receptor Constitutive Active/Androstane Receptor-Mediated Transcription

Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

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.