TY - JOUR T1 - Coordinated Transcriptional Regulation of Cytochrome P450 3As by Nuclear Transcription Factor Y (NF-Y) and Specificity Protein 1 (Sp1) JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.118.114439 SP - mol.118.114439 AU - Yiqun Deng AU - Jikai Wen AU - Ruohong Chen AU - Jiang Jun AU - Zhangsheng Hu AU - Wenchu Ye AU - Qianqian Yuan AU - Mengyuan Li Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/02/19/mol.118.114439.abstract N2 - The cytochrome P450 (CYP) 3A subfamily plays vital roles in the metabolism of endogenous chemicals and xenobiotics. To understand the basal expression of CYP3As in humans and pigs are crucial for drug evaluation. In this study, we determined that the basal transcriptional regulation of CYP3A in hepatocytes is evolutionarily conserved. The basal expressions of CYP3As are transactivated by two cis-acting elements, the CCAAT box and GC box, in the proximal promoter region of six CYP3A genes at a constant distance. The mutagenesis of these two cis-acting elements suggested that they play significant roles in the basal expression but have the different extents because of the nucleotide variations in the elements. Two transcription factors, NF-Y and Sp1, directly bind to these cis-acting elements in the CYP3A proximal promoters in HepG2 cells and porcine hepatocytes. Furthermore, the changes of the distance between the NF-Y and Sp1 binding sites resulted in significant decreases in the promoter activity of CYP3As. conclusively, our results show that human and porcine CYP3As are regulated by NF-Y and Sp1 in a coordinated manner, and the distance between these two cis-acting elements is crucial for their constitutive expressions. ER -