title: Characterization of ligand-dependent activation of bovine and pig constitutive androstane (CAR) and pregnane X receptors (PXR) with interspecies comparisons.
abstract: 1. Nuclear receptors CAR (NR1I3) and PXR (NR1I2) are major ligand-activated transcriptional regulators of xenobiotic metabolism and disposition and modulators of endobiotic metabolism. Differences in xenobiotic selectivity between the human and rodent receptors are well recognized but there is lack of such information on properties of CAR and PXR in important domestic animals. 2. The pig and bovine receptors were cloned and their ligand profiles were systematically compared to corresponding human and mouse forms utilizing a panel of xenobiotics and structural analysis. 3. Pig CAR and PXR resemble their human counterparts which can be rationalized by only modest amino acid changes between critical residues of the human ligand-binding pockets (H203Q for CAR, L210V and M243I for PXR). 4. In contrast, bovine CAR shows a blunted response to CAR agonists and inverse agonists. These changes are likely due to disruptive mutations at or near critical hydrogen bond-forming residues (N165I, Y326F). The unresponsiveness of bovine PXR to human- and mouse-selective agonists may be related to substitutions at important ligand-contacting residues R410Q and F305V, respectively. 5. Our findings have implications for regulation of drug-metabolizing enzymes and transporters and pharmacokinetics in cattle and pigs.
authors.affiliation: a Faculty of Health Sciences , School of Pharmacy, University of Eastern Finland and Biocenter Kuopio , Kuopio , Finland .
authors.forename: Jenni
authors.initials: J
authors.lastname: Küblbeck
authors.affiliation: b Division of Veterinary Pharmacology and Toxicology , Department of Comparative Biomedicine and Food Science, University of Padova , Padova , Italy , and.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zancanella
authors.affiliation: a Faculty of Health Sciences , School of Pharmacy, University of Eastern Finland and Biocenter Kuopio , Kuopio , Finland .
authors.forename: Viktoria
authors.initials: V
authors.lastname: Prantner
authors.affiliation: a Faculty of Health Sciences , School of Pharmacy, University of Eastern Finland and Biocenter Kuopio , Kuopio , Finland .
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Molnár
authors.affiliation: c Department of Animal and Poultry Science , University of Guelph , Guelph , ON , Canada.
authors.forename: E James
authors.initials: EJ
authors.lastname: Squires
authors.affiliation: b Division of Veterinary Pharmacology and Toxicology , Department of Comparative Biomedicine and Food Science, University of Padova , Padova , Italy , and.
authors.forename: Mauro
authors.initials: M
authors.lastname: Dacasto
authors.affiliation: a Faculty of Health Sciences , School of Pharmacy, University of Eastern Finland and Biocenter Kuopio , Kuopio , Finland .
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
authors.affiliation: b Division of Veterinary Pharmacology and Toxicology , Department of Comparative Biomedicine and Food Science, University of Padova , Padova , Italy , and.
authors.forename: Mery
authors.initials: M
authors.lastname: Giantin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D003001:Cloning, Molecular; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation; D006801:Humans; D008658:Inactivation, Metabolic; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013552:Swine
chemical_list: D000090702:Constitutive Androstane Receptor; D008024:Ligands; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; C000625853:Nr1i2 protein, mouse; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid
keywords: Bovine; cytochrome P450; human; induction; ligand-binding domain; mouse; nuclear receptors; pig