title: 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.
authors: Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, 127 Chang Le Xi Road, Xi'an, Shaanxi 710032, China.
authors: Yin
authors: Y
authors: Wu
authors: Xiaopeng
authors: X
authors: Shi
authors: Yonghong
authors: Y
authors: Liu
authors: Xianzhi
authors: X
authors: Zhang
authors: Jinwen
authors: J
authors: Wang
authors: Xiaoxing
authors: X
authors: Luo
authors: Aidong
authors: A
authors: Wen
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000927:Anticonvulsants; D004268:DNA-Binding Proteins; D000077297:Pregnane X Receptor; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1