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Updated: May 6, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

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Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes

Tatsuya Sueyoshi1, Linhao Li, Hongbing Wang

  • 1Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology and.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|November 13, 2013
PubMed

Insights

Polybrominated diphenyl ether BDE-47 activates the human constitutive activated/androstane receptor (CAR), leading to the induction of CYP genes. This finding provides new insights into the mechanism of BDE-47

Area of Science:

  • Environmental Toxicology
  • Molecular Pharmacology
  • Hormone Disruption

Background:

  • Polybrominated diphenyl ether BDE-47 is a known thyroid hormone disruptor in mice.
  • Hepatic induction of metabolic enzymes and transporters is a proposed mechanism for BDE-47's disruptive effects.
  • The roles of constitutive activated/androstane receptor (CAR) and pregnane X receptor (PXR) in mediating these effects are not fully understood.

Purpose of the Study:

  • To investigate the role of CAR and PXR in mediating the effects of BDE-47.
  • To elucidate the mechanism by which BDE-47 induces metabolic enzymes in both mouse and human systems.

Main Methods:

  • Utilized constitutive activated/androstane receptor (CAR) knockout (Car-/-) and pregnane X receptor knockout (Pxr-/-) mice.
  • Employed primary human hepatocytes and luciferase-reporter assays using Huh-7 cells.
  • Investigated the translocation of YFP-tagged human CAR and the expression of CYP2B6 and CYP3A4 mRNAs.

Main Results:

  • BDE-47 activated both mouse and human CAR.
  • In mouse livers, CAR mediated BDE-47-induced Cyp2b10 mRNA expression, not PXR.
  • BDE-47 induced translocation of human CAR and increased CYP2B6 and CYP3A4 mRNA levels in human hepatocytes.
  • Human CAR activation by BDE-47 mimicked the effect of CITCO, while mouse CAR showed weaker activation.
  • Human PXR was effectively activated by BDE-47, whereas mouse PXR showed weak activation.

Conclusions:

  • BDE-47 induces CYP genes through the activation of human CAR, in addition to the previously identified pathway via human PXR.
  • These findings highlight species-specific differences in CAR and PXR activation by BDE-47.
  • The study provides a clearer understanding of the molecular mechanisms underlying BDE-47's endocrine-disrupting potential.
Keywords:
CARPBDEPXRxenobiotic receptor.

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