Histone deacetylase 1 is required for Carbamazepine-induced CYP3A4 expression

Abstract

Carbamazepine (CBZ) is a commonly prescribed antiepileptic drug. Adverse effects and drug–drug interaction are the two major concerns for its clinic application. CBZ is mainly metabolized by cytochrome P450 (CYP) 3A4, a strong inducer of CYP3A4 as well, which in turn influences the pharmaceutical profiles of the co-administrated drugs. To date, little is known about the mechanisms underlying CBZ-induced CYP3A4 expression. In this study, we explored the possible roles of Pregnane X receptor (PXR) and the histone deacetylase 1 (HDAC1) on the CBZ-induced CYP3A4 expression. The results showed that: (1) Although the expression of PXR was increased in CBZ treated cells, PXR gene silencing surprisingly showed no significant effects on CBZ-induced CYP3A4 expression; (2) CBZ inhibited the binding of HDAC1 to the promoter of CYP3A4. In addition, both dominant negative form and siRNA of HDAC1 could repress the CBZ-induced CYP3A4 expression. These data, for the first time indicate that HDAC1, is required for the CBZ-induced CYP3A4 expression.