title: Role of Specificity Protein 1, Hepatocyte Nuclear Factor 1α, and Pregnane X Receptor in the Basal and Rifampicin-Induced Transcriptional Regulation of Porcine Cytochrome P450 3A46.
abstract: Cytochrome P450 (CYP) 3A46, one of human CYP3A4 homologs, functions as a key enzyme in the metabolism of xenobiotics in pigs. However, the regulatory mechanism for the transcriptional activation of CYP3A46 in porcine liver remains unknown. In this study, we confirmed that CYP3A46 is constitutively expressed in porcine primary hepatocytes, and its expression was significantly induced by rifampicin (RIF) instead of dexamethasone. We further found that a proximal GC box and a distal hepatocyte nuclear factor 1 (HNF1) binding site within the 5'-flanking region of CYP3A46 are the important cis-regulatory elements involved in regulating the constitutive expression of CYP3A46, via recruiting specificity protein 1 (Sp1) and HNF1α, respectively. Furthermore, we revealed that HNF1α and pregnane X receptor (PXR) activate the RIF-mediated transcription of CYP3A46 by binding to the distal HNF1 binding site and the proximal direct repeats of AGGTCA separated by 4 bases motif, respectively. Meanwhile, HNF1α is also involved in regulating RIF-induced expression of CYP3A4 through a novel distal HNF1 binding site identified in the xenobiotic-responsive enhancer module. In summary, our data demonstrate that several transcription factors, including Sp1, HNF1α, and PXR, function in the basal and RIF-mediated transcriptional regulation of CYP3A46 by binding to their related cis-regulatory elements in the proximal promoter and distal enhancer.
authors.affiliation: Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, Guangdong, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Dong
authors.affiliation: Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, Guangdong, China.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, Guangdong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, Guangdong, China.
authors.forename: Jikai
authors.initials: J
authors.lastname: Wen
authors.affiliation: Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, Guangdong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou, Guangdong, China yqdeng@scau.edu.cn jiangjun@scau.edu.cn.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000502:physiology*; D006801:Humans; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000502:physiology*; D012293:Rifampin / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000502:physiology*; D013552:Swine
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D016329:Sp1 Transcription Factor; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin