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Estrogens and antiestrogens activate hPXR.

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Many compounds that bind estrogen receptors (ER) also activate the pregnane X receptor (PXR). This dual activation by environmental chemicals and drugs highlights potential health implications.

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Area of Science:

  • Endocrinology
  • Pharmacology
  • Environmental Health

Background:

  • The pregnane X receptor (PXR) and estrogen receptors (ERalpha, ERbeta) bind diverse compounds, including drugs and environmental pollutants.
  • The structural diversity of known ligands for PXR and ER prompted an investigation into potential overlapping functions.

Purpose of the Study:

  • To determine if known estrogen receptor (ER) ligands can activate the pregnane X receptor (PXR).
  • To analyze a range of estrogenic compounds, including natural and synthetic estrogens, antiestrogens, mycoestrogens, phthalates, and alkylphenols for PXR activation.
  • To assess the induction of key drug-metabolizing enzymes (cytochrome P450 3A4 and 2B6) by identified PXR activators in human hepatocytes.

Main Methods:

  • Utilized stably transfected HGPXR cells expressing a chimeric human PXR (hPXR) and luciferase reporter gene to screen compound activation.
  • Tested nearly 50 compounds with known estrogenic activity or ER-binding ability for their capacity to activate hPXR.
  • Assessed the induction of CYP3A4 and CYP2B6 gene expression in primary human hepatocytes for selected hPXR activators.

Main Results:

  • A significant percentage (54%) of compounds with estrogenic activity or ER-binding capacity were identified as hPXR activators.
  • Antiestrogens, mycoestrogens, and phthalates demonstrated notable hPXR activation.
  • The proportion of hPXR activators increased when estrogenic pesticides were included in the analysis.

Conclusions:

  • Estrogenic compounds can possess dual activity, activating both ER and PXR.
  • The overlap in ligand binding suggests potential for complex biological responses to environmental chemicals and drugs.
  • Further investigation is warranted to understand the implications of dual PXR/ER activation by various compounds.