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Updated: Mar 25, 2026

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The pregnane X receptor down-regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for

Lucie Hyrsova1, Tomas Smutny1, Alejandro Carazo1

  • 1Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.

British Journal of Pharmacology
|February 28, 2016
PubMed
Abstract

Insights

Pregnane X receptor (PXR) activation down-regulates organic cation transporter 1 (OCT1) in hepatocytes. This occurs by PXR competing for the SRC-1 coactivator, reducing drug transport into liver cells.

Area of Science:

  • Hepatology
  • Molecular Pharmacology
  • Drug Metabolism

Background:

  • Organic cation transporter 1 (OCT1) is crucial for hepatic drug uptake.
  • OCT1 expression is regulated by transcription factors HNF4α and USF.
  • Pregnane X receptor (PXR) controls xenobiotic metabolism and transport in the liver.

Purpose of the Study:

  • To investigate the down-regulation of OCT1 expression by PXR activation.
  • To elucidate the molecular mechanisms underlying PXR-mediated OCT1 repression.

Main Methods:

  • Primary human hepatocytes and HepaRG cells were used to assess OCT1 expression and activity.
  • Techniques included Western blotting, qRT-PCR, promoter-reporter assays, and chromatin immunoprecipitation.
  • MPP(+) accumulation assays measured OCT1 transporter activity.

Main Results:

  • PXR activation by rifampicin and hyperforin reduced OCT1 mRNA and MPP(+) uptake in hepatocytes.
  • PXR ligands suppressed OCT1 promoter activity, dependent on HNF4α and USF binding sites.
  • PXR activation sequestered the SRC-1 coactivator from OCT1 promoter elements, inhibiting transcription.

Conclusions:

  • PXR activation inhibits OCT1 gene expression by competing with HNF4α and USF for the SRC-1 coactivator.
  • This mechanism reduces the hepatic delivery of OCT1 substrates, impacting drug disposition.

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