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Quantitative profiling of environmental chemicals and drugs for farnesoid X receptor activity

Tuesday, September 23, 2014 — Poster Session III

12:00 p.m. – 2:00 p.m.

FAES Academic Center




  • CW Hsu
  • J Zhao
  • R Huang
  • JH Hsieh
  • JT Hamm
  • X Chang
  • KA Houck
  • M Xia


Farnesoid X receptor (FXR), a bile acid sensor, exerts protective function in numerous diseases including cholestasis, diabetes, liver regeneration, and cancer. Despite the extensive interests in FXR ligands in drug discovery, little is known regarding potential FXR-mediated toxicity effects from xenobiotic chemicals. Here we describe the profiling of approximately 10K environmental chemicals and drugs in modifying FXR signaling and associated cytotoxicity. The FXR beta-lactamase assay was used to screen the Tox21 10K compound library, containing environmental chemicals, clinically-approved drugs and known bioactive small molecules, in a 1536-well plate format at 15 concentrations in triplicate runs. 435 potent and reproducible hits were identified and grouped into several clusters based on their chemical structure similarity and known biological function. Many environmental chemicals including synthetic hormones, pesticides, and industrial chemicals showed FXR antagonist activity. Some drugs acted as agonists, antagonists, or partial agonists of FXR. Several clusters of compounds identified from the screening were also found to be active against other functionally related nuclear receptors. These results not only provide directions for prioritizing chemicals for further testing FXR-mediated toxicity but also suggest novel signaling pathways for future mechanistic studies.

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