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Submitted on October 20, 2004
Accepted on February 11, 2005
Department of Pathology, Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL 60637, USA; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Zoological Society of San Diego, San Diego, CA 92112 and Department of Medicine, University of California, San Diego, CA, 92093, USA
* To whom correspondence should be addressed. E-mail: kra3{at}harper.uchicago.edu.
The pregnane X receptor (PXR) regulates the metabolism and elimination of bile salts, steroids, and xenobiotics. The sequence of the PXR ligand-binding domain diverges extensively between different animals suggesting inter-species differences in ligands. Of the endogenous ligands known to activate PXR, biliary bile salts vary the most across vertebrate species, ranging from 27-carbon (C27) bile alcohol sulfates (early fish, amphibians) to C24 bile acids (birds, mammals). Using a luciferase-based reporter assay, human PXR was activated by a wide variety of bile salts. In contrast, zebrafish PXR was activated efficiently only by cyprinol sulfate, the major zebrafish bile salt, but not by recent bile acids. Chicken, mouse, rat, and rabbit PXRs were all activated by species-specific bile acids and by early fish bile alcohol sulfates. In addition, phylogenetic analysis using maximum likelihood demonstrated evidence for non-neutral evolution of the PXR ligand-binding domain. PXR activation by bile salts has expanded from narrow specificity for C27 bile alcohol sulfates (early fish) to a broader specificity for recent bile acids (birds, mammals). PXR specificity for bile salts has thus paralleled the increasing complexity of the bile salt synthetic pathway during vertebrate evolution, an unusual example of ligand-receptor co-evolution in the nuclear hormone receptor superfamily.
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