RT Journal Article SR Electronic T1 Inhibition of Human UGT2B7 Gene Expression in Transgenic Mice by the Constitutive Androstane Receptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.110.070649 DO 10.1124/mol.110.070649 A1 Mei-Fei Yueh A1 Pamela L Mellon A1 Robert H Tukey YR 2011 UL http://molpharm.aspetjournals.org/content/early/2011/03/17/mol.110.070649.abstract AB The xenobiotic receptors (XenRs), constitutive androstane receptor (CAR), and pregnane X receptor (PXR) regulate and alter the metabolism of xenobiotic substrates. Among the 19 functional UDP-glucuronosyltransferases (UGTs) in humans, UGT2B7 is involved in the metabolism of many structurally diverse xenobiotics and plays an important role in the clearance and detoxification of many therapeutic drugs. To examine if this gene is regulated by CAR and PXR in vivo, transgenic mice expressing the entire UGT2B7 gene (TgUGT2B7) were created. Gene expression profiles revealed that UGT2B7 is differentially expressed in liver, kidney, adipocytes, brain, and estrogen-sensitive tissues, such as ovary and uterus. Liver UGT2B7 expression levels were decreased when TgUGT2B7 mice were treated with the CAR ligand 1, 4-b-s-[2-(3, 5,-dichloropyridyloxy)] (TCPOBOP), but not the PXR ligand pregnenalone 16α-carbonitrile. While TCPOBOP decreased the levels of UGT2B7 mRNA in TgUGT2B7 mice it had no impact on Tg(UGT2B7)Car-/- mice, adding support for a CAR-dependent mechanism contributing towards UGT2B7 gene suppression. Expression of promoter constructs in HepG2 cells showed the CAR dependent inhibition was linked to HNF4 α-mediated transactivation of the UGT2B7 promoter. The inhibitory effect of CAR on UGT2B7 gene expression was validated in CHIP assays in which TCPOBOP treatment blocked HNF4α binding to the UGT2B7 promoter. These results suggest that HNF4α plays an important role in the constitutive expression of hepatic UGT2B7, and CAR acts as a negative regulator by interfering with HNF4α binding activity.