A CAR-responsive enhancer element locating approximately 31 kb upstream in the 5'-flanking region of rat cytochrome P450 (CYP) 3A1 gene.
Constitutive androstane receptor (CAR) is one of the principal regulators of hepatic cytochrome P450s (CYPs) 3A (CYP3A). cDNA-mediated expression of a mature rat CAR (rCAR) into rat hepatoma cells induced CYP3A1 and CYP2B mRNAs. Aberrant rCAR failed in these inductions. Three important human CYP3A4 regulatory elements (REs), proximal ER6 (proER6), xenobiotic responsive enhancer module (XREM) and constitutive liver enhancer module (CLEM), support constitutive and inducible expression of CYP3As mediated by CAR and pregnane X receptor (PXR). NHR-scan software predicted proER6, XREM and CLEM at -255 b, -8 kb and -11.5 kb, respectively of CYP3A4, but neither XREM nor CLEM was predicted in rat CYP3A. A luciferase reporter construct carrying a 5'-flanking sequence of CYP3A1 (-31,739 to -31,585 from its transcription initiation site) revealed important for the rCAR-dependent transactivation of CYP3A1. This region includes two putative binding motifs of nuclear receptors (DR4 and DR2), a putative hepatocyte nuclear factor-1 binding motif (HNF1), nuclear factor-kappa B binding motif (NFκB), activator protein 1 binding motif (AP-1), and ecotropic viral integration site 1 binding motif (Evi1). We hereby conclude DR4 and/or DR2 motifs being primarily responsible and HNF1 being synergistically functioning elements for the rCAR-mediated transcription of CYP3A1.
['Gamou|Toshie|T|', 'Habano|Wataru|W|', 'Terashima|Jun|J|', 'Ozawa|Shogo|S|']
D024506:5' Flanking Region D000818:Animals D001665:Binding Sites D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D000090702:Constitutive Androstane Receptor D051544:Cytochrome P-450 CYP3A D003907:Dexamethasone D015971:Gene Expression Regulation, Enzymologic D017930:Genes, Reporter D051537:Hepatocyte Nuclear Factor 1 D022781:Hepatocytes D008113:Liver Neoplasms D008297:Male D011485:Protein Binding D012333:RNA, Messenger D011916:Rats, Inbred F344 D018160:Receptors, Cytoplasmic and Nuclear D020218:Response Elements D014158:Transcription, Genetic D015533:Transcriptional Activation D014162:Transfection D014233:Tricarboxylic Acids
Cytochrome P450 Constitutive androstane receptor (CAR) Nuclear receptor CYP3A family Enzyme induction