title: Evolution of the pregnane x receptor: adaptation to cross-species differences in biliary bile salts.
abstract: 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.
authors.affiliation: University of Pittsburgh, Department of Pathology, 200 Lothrop, Pittsburgh, PA 15213, USA. kra3@uchicago.edum
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Krasowski
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yasuda
authors.forename: Lee R
authors.initials: LR
authors.lastname: Hagey
authors.forename: Erin G
authors.initials: EG
authors.lastname: Schuetz
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D002777:Cholestanols / Q000494:pharmacology; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010802:Phylogeny; D000077297:Pregnane X Receptor; D011817:Rabbits; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000145:classification* / Q000187:drug effects / Q000235:genetics; D011987:Receptors, Steroid / Q000819:agonists* / Q000145:classification* / Q000235:genetics; D013045:Species Specificity; D029867:Xenopus Proteins / Q000187:drug effects; D014982:Xenopus laevis; D015027:Zebrafish
chemical_list: D001647:Bile Acids and Salts; D002777:Cholestanols; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D029867:Xenopus Proteins; C112210:benzoate X receptor, Xenopus; C009561:3,7,12-trihydroxycoprostane
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