The evolution of drug-activated nuclear receptors: one ancestral gene diverged into two xenosensor genes in mammals

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Updated: Aug 21, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

Christoph Handschin, Sharon Blättler, Adrian Roth

    Nuclear Receptor
    |October 14, 2004
    PubMed

    Insights

    Chicken xenobiotic receptor (CXR) is an ancestral gene that evolved into mammalian pregnane X receptor (PXR) and constitutive androstane receptor (CAR). This study identifies CXR as the sole xenosensor in chickens, unlike mammals with two.

    Area of Science:

    • Pharmacology and Toxicology
    • Evolutionary Biology
    • Molecular Biology

    Background:

    • Mammalian drugs and xenobiotics induce cytochrome P450 (CYP) gene expression via pregnane X receptor (PXR) and constitutive androstane receptor (CAR).
    • Non-mammalian species were previously thought to possess only one xenosensor gene.
    • Understanding xenobiotic sensing evolution requires comparative studies across species.

    Purpose of the Study:

    • To investigate whether non-mammalian species possess one or two xenosensor genes, similar to mammals.
    • To functionally and structurally characterize the chicken xenobiotic receptor (CXR).
    • To compare CXR's properties with mammalian PXR and CAR to understand evolutionary divergence.

    Main Methods:

    • Experimental approaches to identify novel xenobiotic sensing nuclear receptors in chickens.
    • RNA interference (RNAi) and dominant-negative alleles to ablate chicken xenobiotic receptor (CXR) function.
    • Functional and structural characterization of CXR, including ligand activation, promiscuity, and cellular localization studies.
    • Comparative analysis of CXR with mammalian PXR and CAR.

    Main Results:

    • No novel xenobiotic sensing nuclear receptors were identified in chickens beyond CXR.
    • Ablation of CXR function significantly reduced drug-induced gene expression in chicken cells.
    • CXR shares ligand activation and promiscuity traits with PXR, but cytoplasmic-nuclear distribution with CAR.
    • CXR exhibits unique regulatory properties distinct from PXR and CAR.

    Conclusions:

    • Chicken xenobiotic receptor (CXR) is suggested to be an ancestral gene.
    • CXR likely evolved into the distinct mammalian PXR and CAR receptors.
    • Further research is needed to understand the evolutionary reasons for this divergence.

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