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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 Receptors in Drug Metabolism, Drug Response and Drug Interactions

Chandra Prakash1, Baltazar Zuniga2, Chung Seog Song3

  • 1Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245; William Carey University College of Osteopathic Medicine, 498 Tucsan Ave, Hattiesburg, Mississipi 39401.

Nuclear Receptor Research
|August 2, 2016
PubMed

Insights

This review explores how nuclear receptors (NRs) like PXR, CAR, and VDR regulate drug-metabolizing enzymes and transporters. Understanding genetic and epigenetic factors is key to personalized medicine and avoiding adverse drug reactions.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Genetics

Background:

  • Orally administered drugs are processed by liver and intestinal enzymes and transporters.
  • Nuclear receptors (NRs) like PXR, CAR, and VDR control genes for drug metabolism and transport.
  • Genetic variations and epigenetics influence drug response.

Purpose of the Study:

  • To review the regulation of drug-metabolizing enzymes (DMEs) and transporters by PXR, CAR, and VDR.
  • To examine the impact of genetic (SNP) and epigenetic factors on DME/transporter expression and drug response.
  • To discuss therapeutic strategies targeting epigenetic regulation and drug interactions.

Main Methods:

  • Literature review of PXR/CAR/VDR-mediated gene regulation.
  • Analysis of single nucleotide polymorphism (SNP) and epigenome effects on drug disposition genes.
  • Discussion of drug-drug, drug-food, and drug-herb interactions.
  • Exploration of novel drug screening models (e.g., organs-on-chips).

Main Results:

  • PXR, CAR, and VDR are key regulators of phase I and II drug-metabolizing enzymes and phase 0-III transporters.
  • SNPs and epigenetic modifications significantly alter the expression of these genes, leading to variable drug responses.
  • Drug interactions can arise from altered DME and transporter activity.

Conclusions:

  • Understanding NR-mediated regulation of DMEs and transporters is crucial for precision medicine.
  • Targeting epigenetic regulation and characterizing interactions are vital for optimizing drug efficacy and safety.
  • Advanced models like organs-on-chips will improve future drug screening.
Keywords:
CARDrug interactionsDrug screeningEpigeneticsGene inductionGenetic polymorphismNuclear receptorsPXRPhase 0-III mediatorsXenobiotic-response element

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