title: Differential modulation of FXR activity by chlorophacinone and ivermectin analogs.
abstract: 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 10K 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.
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors: Chia-Wen
authors: CW
authors: Hsu
authors: National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors: Jui-Hua
authors: JH
authors: Hsieh
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors: Ruili
authors: R
authors: Huang
authors: PamGene International B.V., Wolvenhoek 10, 5211 HH 's-Hertogenbosch, The Netherlands.
authors: Dirk
authors: D
authors: Pijnenburg
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors: Thai
authors: T
authors: Khuc
authors: Integrated Laboratory System, Inc., Morrisville, NC, USA.
authors: Jon
authors: J
authors: Hamm
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors: Jinghua
authors: J
authors: Zhao
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors: Caitlin
authors: C
authors: Lynch
authors: PamGene International B.V., Wolvenhoek 10, 5211 HH 's-Hertogenbosch, The Netherlands.
authors: Rinie
authors: R
authors: van Beuningen
authors: Integrated Laboratory System, Inc., Morrisville, NC, USA.
authors: Xiaoqing
authors: X
authors: Chang
authors: PamGene International B.V., Wolvenhoek 10, 5211 HH 's-Hertogenbosch, The Netherlands.
authors: René
authors: R
authors: Houtman
authors: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA. Electronic address: mxia@mail.nih.gov.
authors: Menghang
authors: M
authors: Xia
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007559:Ivermectin / Q000031:analogs & derivatives / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007189:Indans; D007559:Ivermectin; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C004662:chlorophacinone
keywords: Chlorophacinone; Diphacinone; Farnesoid X receptor; Ivermetin; Moxidectin; Nuclear receptor; Tox21