Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor.



The farnesoid X receptor (FXR) regulates the homeostasis of bile acids, lipids, and glucose. Because endogenous chemicals bind and activate FXR, it is important to examine which xenobiotic compounds would disrupt normal receptor function. We used a cell-based human FXR β-lactamase (Bla) reporter gene assay to profile the Tox21 10K compound collection of environmental chemicals and drugs. Structure-activity relationships of FXR-active compounds revealed by this screening were then compared against the androgen receptor, estrogen receptor α, peroxisome proliferator-activated receptors δ and γ, and the vitamin D receptor. We identified several FXR-active structural classes including anthracyclines, benzimidazoles, dihydropyridines, pyrethroids, retinoic acids, and vinca alkaloids. Microtubule inhibitors potently decreased FXR reporter gene activity. Pyrethroids specifically antagonized FXR transactivation. Anthracyclines affected reporter activity in all tested assays, suggesting non-specific activity. These results provide important information to prioritize chemicals for further investigation, and suggest possible modes of action of compounds in FXR signaling.


Hsu, Chia-Wen; Zhao, Jinghua; Huang, Ruili; Hsieh, Jui-Hua; Hamm, Jon; Chang, Xiaoqing; Houck, Keith; Xia, Menghang;


  • Bile Acids and Salts/ metabolism
  • Binding Sites
  • DNA-Binding Proteins/ genetics
  • Genes, Reporter
  • Glucose/ metabolism
  • HEK293 Cells
  • Humans
  • Lipid Metabolism/ drug effects
  • Promoter Regions, Genetic/ drug effects
  • Receptors, Cytoplasmic and Nuclear/ biosynthesis
  • Receptors, Cytoplasmic and Nuclear/ genetics
  • Signal Transduction
  • Structure-Activity Relationship
  • Xenobiotics/ pharmacology
  • Xenobiotics/ toxicity
  • beta-Lactamases/ biosynthesis
  • beta-Lactamases/ genetics

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