Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10 K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs.

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Date of publication: 20 October 2016 (Online); Toxicology and Applied Pharmacology

Author information: Chia-Wen Hsu (1); Jui-Hua Hsieh (2); Ruili Huang (1); Dirk Pijnenburg (3); Thai Khuc (1); Jon Hamm (4); Jinghua Zhao (1); Caitlin Lynch (1); Rinie van Beuningen (3); Xiaoqing Chang (4); Rene Houtman (3); & Menghang Xia (1)

(1) NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
(2) National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
PamGene International B.V., Wolvenhoek 10, 5211 HH ‘s-Hertogenbosch, The Netherlands
Integrated Laboratory System, Inc., Morrisville, NC, USA


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