New in Vitro Tools to Study Human Constitutive Androstane Receptor (CAR) Biology: Discovery and Comparison of Human CAR Inverse Agonists

Citations Over TimeTop 10% of 2011 papers

Abstract

The human constitutive androstane receptor (CAR, NR1I3) is one of the key regulators of xenobiotic and endobiotic metabolism. The unique properties of human CAR, such as the high constitutive activity and the complexity of signaling, as well as the lack of functional and predictive cell-based assays to study the properties of the receptor, have hindered the discovery of selective human CAR ligands. Here we report a novel human CAR inverse agonist, 1-[(2-methylbenzofuran-3-yl)methyl]-3-(thiophen-2-ylmethyl) urea (S07662), which suppresses human CAR activity, recruits the corepressor NCoR in cell-based assays, and attenuates the phenytoin- and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO)-induced expression of CYP2B6 mRNA in human primary hepatocytes. The properties of S07662 are also compared with those of known human CAR inverse agonists by using an array of different in vitro and in silico assays. The identified compound S07662 can be used as a chemical tool to study the biological functions of human CAR and also as a starting point for the development of new drugs for various conditions involving the receptor.

Related Papers

• → A brief history of the discovery of PXR and CAR as xenobiotic receptors(2016)62 cited
• → Beyond CAR and PXR(2005)27 cited
• → Xenobiotic Receptors, a Journey of Rewards(2022)5 cited
• → Animal Models of Xenobiotic Receptors(2005)17 cited
• → P1.e.002 Activation of the brain serotonergic system decreases the expression and activity of liver cytochrome P450 isoforms CYP1A, 2C11 and 3A(2015)1 cited