RT Journal Article
SR Electronic
T1 Regulation of the CYP3A4 and CYP3A7 Promoters by Members of the Nuclear Factor I Transcription Factor Family
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1104
OP 1114
DO 10.1124/mol.109.055699
VO 76
IS 5
A1 Amanda K. Riffel
A1 Eric Schuenemann
A1 Carrie A. Vyhlidal
YR 2009
UL http://molpharm.aspetjournals.org/content/76/5/1104.abstract
AB Despite the established interindividual variability and ontogeny of the CYP3A enzymes, the most abundant phase I drug-metabolizing enzymes in human liver and intestine, the mechanisms that regulate basal expression remain poorly understood. Electrophoretic mobility shift assays using nuclear proteins extracted from human prenatal and postnatal liver samples identified multiple, developmentally distinct nuclear factor I (NFI)-containing protein complexes from human liver bound to sequences from the CYP3A4 (−243/−220) and CYP3A7 (−242/−219) proximal promoters. In addition, a hepatocyte nuclear factor (HNF) 3γ-containing complex from prenatal liver interacted with CYP3A7−242/−219 but not CYP3A4−243/−220. Cotransfection of HepG2 cells with a CYP3A4 proximal promoter construct and expression vectors for the NFI isoforms NFIA1.1, NFIB2, NFIC1, NFIC2, and NFIX1 enhanced the expression of luciferase activity. In contrast, cotransfection of NFIB2, NFIC1, NFIC2, NFIX1, and NFIX2 reduced the expression of luciferase under the control of the CYP3A7 gene promoter. Mutagenesis of the NFI/HNF3γ binding sites in the CYP3A7 and CYP3A4 proximal promoters suggests that regulation of basal promoter activity by members of the NFI transcription factor family occur via multiple mechanisms. These results demonstrate that members of the NFI transcription factor family regulate CYP3A4 and CYP3A7 basal expression in an isoform- and promoter-specific manner. © 2009 The American Society for Pharmacology and Experimental Therapeutics