Coordinated Transcriptional Regulation of Cytochrome P450 3As by Nuclear Transcription Factor Y and Specificity Protein 1

Abstract

The cytochrome P450 3A subfamily plays vital roles in the metabolism of endogenous chemicals and xenobiotics. Understanding the basal expression of CYP3A in humans and pigs is crucial for drug evaluation. In this study, we demonstrated that the basal transcriptional regulation of CYP3A genes in hepatocytes is evolutionarily conserved between humans and pigs. The basal expression of CYP3A genes is transactivated by two cisacting elements, the CCAAT and GC boxes, located a constant distance apart in the proximal promoter region of six CYP3A genes. Mutation analysis of these two cis-acting elements suggested that they play important roles in mediating basal expression, but to different extents because of the nucleotide variations in the elements. Two transcription factors, nuclear transcription factor Y (NF-Y) and specificity protein 1 (Sp1), directly bind to these cis-acting elements in CYP3A proximal promoters in HepG2 cells and porcine hepatocytes. Furthermore, changing the distance between the NF-Y and Sp1 binding sites resulted in decreases in the promoter activity of CYP3A genes. Conclusively, our results show that human and porcine CYP3A genes are regulated by NF-Y and Sp1 in a coordinated manner, and that the distance between these two cis-acting elements is crucial for constitutive CYP3A expression.

Epigenetically inhibiting CYP3A5 modulates the migration and invasion of esophageal squamous cell carcinoma via ZEB2

“…Transcriptional regulation of CYP3A5 has not been widely investigated. Only a few nuclear receptors, such as NF-Y [47], SP1 [47], CAR [48], AR [49], HNF-4α, and PXR/ RXRα [50] have been identi ed as possible factors involved in the transcriptional expression of CYP3A5, mainly in liver and prostate cancer. Nuclear receptors regulate transcription by binding to DNA response elements (AGGTCA half-sites).…”

The Reduction of the Combined Effects of Aflatoxin and Ochratoxin A in Piglet Livers and Kidneys by Dietary Antioxidants

“…Previous works have demonstrated that CYP3A constitutive expression is regulated by nuclear transcription factor Y; specificity protein 1 [81,82]; hepatocyte nuclear factors 1α, 3γ and 4 [83][84][85]; upstream stimulatory factor 1 [86]; activator protein 1 [87] and CCAAT/enhancer-binding proteins α and β [85,86]. In the presence of xenobiotics, induced expression of CYP3A is mediated by Pregnane X Receptor [80], constitutive androstane receptor (CAR), glucocorticoid receptor (GR) and vitamin D receptor (VDR) [81,88,89].…”