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Identification of pregnane-X receptor target genes and coactivator and corepressor binding to promoter elements in

Niresh Hariparsad1, Xiaoyan Chu, Jocelyn Yabut

  • 1Department of Drug Metabolism and Pharmacokinetics, Merck & Co, Rahway, NJ 07065, USA. niresh_hariparsad@merck.com

Nucleic Acids Research
|January 9, 2009
PubMed

Insights

This study identified new drug disposition genes regulated by the pregnane-X receptor (PXR). While PXR and SRC-1 bind many gene promoters, only CYP4F12 showed increased binding with rifampicin.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Genetics

Background:

  • The pregnane-X receptor (PXR) is a key regulator of drug metabolism and disposition.
  • Identifying novel PXR target genes is crucial for understanding drug response variability.

Purpose of the Study:

  • To identify new drug disposition genes regulated by PXR using chromatin immunoprecipitation (ChIP).
  • To investigate the role of PXR in the regulation of CYP4F12 and its interaction with coactivators/corepressors.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) in human hepatocytes treated with rifampicin.
  • Identification and validation of PXR response elements (PXREs).
  • PXR silencing experiments and assessment of coactivator/corepressor binding.

Main Results:

  • Several new drug disposition genes with PXR binding sites were identified.
  • CYP4F12 demonstrated increased PXR binding in the presence of rifampicin, confirmed by silencing studies.
  • PXR and SRC-1 bind to a broad range of promoters, but not all are rifampicin-inducible.

Conclusions:

  • PXR plays a significant role in regulating CYP4F12 expression.
  • PXR and SRC-1 exhibit broad promoter binding, with context-dependent coactivator/corepressor interactions.
  • Rifampicin induces PXR binding to specific target genes, highlighting its role in drug metabolism regulation.

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