Histone Deacetylase Inhibitors Induce Cytochrome P450 2B by Activating Nuclear Receptor Constitutive Androstane Receptor

Valproic acid, a histone deacetylase (HDAC) inhibitor, induces the cytochrome P450 2B subfamily. However, the effects of HDAC inhibitors on CYP2B induction are still not fully understood. Nuclear receptor constitutive androstane receptor (CAR) is a key regulator of CYP2B induction. In this study, we investigated the effect of HDAC inhibitors on CAR-mediated CYP2B induction. The expression of CYP2B6 mRNA was induced in HepG2 cells stably expressing mouse CAR (Ym17) by HDAC inhibitors including valproic acid, phenylbutyrate, and trichostatin A. HDAC inhibitors activated the phenobarbital-responsive enhancer module of the CYP2B6 promoter in transient transfection reporter assays with Ym17 cells. Furthermore, HDAC inhibitors synergistically augmented the effect of the CAR ligand, 1,4-bis[2-(3,5-dichloropyri-dyloxy)]benzene, in the transactivation of CYP2B6 mRNA and the promoter assay in Ym17 cells. Intraperitoneal injection of HDAC inhibitors induced Cyp2b10 mRNA in wild-type mice. However, such induction was not observed in CAR(-/-) mice. Immunoprecipitation demonstrated that CAR formed a complex with HDACs. HDAC inhibitors diminished the binding between CAR and HDAC1 and augmented the binding of steroid receptor coactivator-1 (SRC-1) to CAR. Furthermore, small interfering RNA knockdown of HDAC1 increased CYP2B6 mRNA expression. These results provide novel insight into the mechanism by which HDAC inhibitors affect gene expression of CYP2B6. HDAC inhibitors have the potential to up-regulate CYP2B6 through the dissociation of HDAC1 and recruitment of SRC-1 to receptor CAR.