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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Nuclear receptor-mediated regulation of carboxylesterase expression and activity

Jeff L Staudinger1, Chenshu Xu, Yue J Cui

  • 1Department of Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA. stauding@ku.edu

Expert Opinion on Drug Metabolism & Toxicology
|February 19, 2010
PubMed
Abstract

Insights

Nuclear receptors (NRs) regulate carboxylesterase (CES) enzymes crucial for drug metabolism. Understanding NR-mediated CES regulation impacts drug design and combination therapies.

Area of Science:

  • Pharmacology
  • Toxicology
  • Drug Metabolism

Background:

  • Nuclear receptors (NRs) influence carboxylesterase (CES) enzyme activity in mammalian liver and intestine.
  • CES enzymes metabolize anticancer prodrugs, insecticides, toxicants, and are key in drug design strategies.

Purpose of the Study:

  • To review NR-mediated regulation of CES enzymes in mammals.
  • To highlight the role of CES enzymes in drug metabolism, drug-drug interactions, and toxicology.

Main Methods:

  • Review of current literature on NR-mediated regulation of CES enzymes.
  • Analysis of data from knockout and transgenic mouse models.

Main Results:

  • Pregnane X receptor (NR1I2) and constitutive androstane receptor (NR1I3) transcriptional regulation of CES enzymes elucidated.
  • Species-specific cross-regulation of glucocorticoid receptor (NR3C1) and PPAR-alpha (NR1C1) signaling with CES gene expression discussed.

Conclusions:

  • Understanding NR-mediated regulation of CES enzymes is vital for rational drug design.
  • This knowledge will significantly impact the development of novel prodrugs, particularly for combination therapy patients.

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