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Molecular Endocrinology, doi:10.1210/me.2004-0427
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Molecular Endocrinology 19 (7): 1720-1739
Copyright © 2005 by The Endocrine Society

Evolution of the Pregnane X Receptor: Adaptation to Cross-Species Differences in Biliary Bile Salts

Matthew D. Krasowski, Kazuto Yasuda, Lee R. Hagey and Erin G. Schuetz

Department of Pathology and Committee on Clinical Pharmacology and Pharmacogenomics (M.D.K.), University of Chicago, Chicago, Illinois 60637; Department of Pharmaceutical Sciences (K.Y., E.G.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; Zoological Society of San Diego (L.R.H.), San Diego, California 92112; and Department of Medicine (L.R.H.), University of California San Diego, San Diego, California 92093

Address all correspondence and requests for reprints to: Matthew D. Krasowski, M.D., Ph.D., University of Pittsburgh, Department of Pathology, 200 Lothrop, Pittsburgh, Pennsylvania 15213. E-mail: kra3{at}uchicago.edum or erin.schuetz{at}stjude.org.

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 interspecies 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 nonneutral 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 coevolution in the nuclear hormone receptor superfamily.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  PXR  |  CAR
Ligands:   Rifampicin  |  Calcitriol  |  Hyperforin  |  Androstanol  |  SR12813



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