This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 19/7/1720    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krasowski, M. D. Articles by Schuetz, E. G. Search for Related Content PubMed PubMed Citation Articles by Krasowski, M. D. Articles by Schuetz, E. G.

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

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

This article has been cited by other articles:

				E. J. Reschly, N. Ai, S. Ekins, W. J. Welsh, L. R. Hagey, A. F. Hofmann, and M. D. Krasowski Evolution of the bile salt nuclear receptor FXR in vertebrates J. Lipid Res., July 1, 2008; 49(7): 1577 - 1587. [Abstract] [Full Text] [PDF]

				D. C. Volz, S. W. Kullman, D. L. Howarth, R. C. Hardman, and D. E. Hinton Protective Response of the Ah Receptor to ANIT-Induced Biliary Epithelial Cell Toxicity in See-Through Medaka Toxicol. Sci., April 1, 2008; 102(2): 262 - 277. [Abstract] [Full Text] [PDF]

				S. Ekins, C. Chang, S. Mani, M. D. Krasowski, E. J. Reschly, M. Iyer, V. Kholodovych, N. Ai, W. J. Welsh, M. Sinz, et al. Human Pregnane X Receptor Antagonists and Agonists Define Molecular Requirements for Different Binding Sites Mol. Pharmacol., September 1, 2007; 72(3): 592 - 603. [Abstract] [Full Text] [PDF]

				Y. Xue, L. B. Moore, J. Orans, L. Peng, S. Bencharit, S. A. Kliewer, and M. R. Redinbo Crystal Structure of the Pregnane X Receptor-Estradiol Complex Provides Insights into Endobiotic Recognition Mol. Endocrinol., May 1, 2007; 21(5): 1028 - 1038. [Abstract] [Full Text] [PDF]

				H. Sakai, H. Iwata, E.-Y. Kim, O. Tsydenova, N. Miyazaki, E. A. Petrov, V. B. Batoev, and S. Tanabe Constitutive Androstane Receptor (CAR) as a Potential Sensing Biomarker of Persistent Organic Pollutants (POPs) in Aquatic Mammal: Molecular Characterization, Expression Level, and Ligand Profiling in Baikal Seal (Pusa sibirica) Toxicol. Sci., November 1, 2006; 94(1): 57 - 70. [Abstract] [Full Text] [PDF]

				J. Orans, D. G. Teotico, and M. R. Redinbo The Nuclear Xenobiotic Receptor Pregnane X Receptor: Recent Insights and New Challenges Mol. Endocrinol., December 1, 2005; 19(12): 2891 - 2900. [Abstract] [Full Text] [PDF]

				S. Chen, D. Beaton, N. Nguyen, K. Senekeo-Effenberger, E. Brace-Sinnokrak, U. Argikar, R. P. Remmel, J. Trottier, O. Barbier, J. K. Ritter, et al. Tissue-specific, Inducible, and Hormonal Control of the Human UDP-Glucuronosyltransferase-1 (UGT1) Locus J. Biol. Chem., November 11, 2005; 280(45): 37547 - 37557. [Abstract] [Full Text] [PDF]

				G. S. Shelness and L. L. Rudel A Role for the Pregnane X Receptor in High-Density Lipoprotein Metabolism Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2016 - 2017. [Full Text] [PDF]

				D. Masson, L. Lagrost, A. Athias, P. Gambert, C. Brimer-Cline, L. Lan, J. D. Schuetz, E. G. Schuetz, and M. Assem Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid-Mediated Changes in Plasma Lipoprotein Profile Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2164 - 2169. [Abstract] [Full Text] [PDF]