title: Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently.
abstract: BACKGROUND
  Many persistent organic pollutants (POPs) accumulate readily in polar bears because of their position as apex predators in Arctic food webs. The pregnane X receptor (PXR, formally NR1I2, here proposed to be named promiscuous xenobiotic receptor) is a xenobiotic sensor that is directly involved in metabolizing pathways of a wide range of environmental contaminants.
  
  
  OBJECTIVE
  In the present study, we comparably assess the ability of 51 selected pharmaceuticals, pesticides and emerging contaminants to activate PXRs from polar bears and humans using an in vitro luciferase reporter gene assay.
  
  
  RESULTS
  We found that polar bear PXR is activated by a wide range of our test compounds (68%) but has a slightly more narrow ligand specificity than human PXR that was activated by 86% of the 51 test compounds. The majority of the agonists identified (70%) produces a stronger induction of the reporter gene via human PXR than via polar bear PXR, however with some notable and environmentally relevant exceptions.
  
  
  CONCLUSIONS
  Due to the observed differences in activation of polar bear and human PXRs, exposure of each species to environmental agents is likely to induce biotransformation differently in the two species. Bioinformatics analyses and structural modeling studies suggest that amino acids that are not part of the ligand-binding domain and do not interact with the ligand can modulate receptor activation.
authors: University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen, Norway. Electronic address: Roger.lille-langoy@bio.uib.no.
authors: Roger
authors: R
authors: Lille-Langøy
authors: Woods Hole Oceanographic Institution, 266 Woods Hole Road, 02543-1050 Woods Hole, MA, USA.
authors: Jared V
authors: JV
authors: Goldstone
authors: University of Bergen, Department of Molecular Biology, P.O. Box 7803, N-5020 Bergen, Norway.
authors: Marte
authors: M
authors: Rusten
authors: Mars Hill University, 100 Athletic Street, Box 6671, Mars Hill, 28754 NC, USA.
authors: Matthew R
authors: MR
authors: Milnes
authors: University of Bergen, Department of Molecular Biology, P.O. Box 7803, N-5020 Bergen, Norway.
authors: Rune
authors: R
authors: Male
authors: Woods Hole Oceanographic Institution, 266 Woods Hole Road, 02543-1050 Woods Hole, MA, USA.
authors: John J
authors: JJ
authors: Stegeman
authors: University of California, Irvine, 92697 CA, USA.
authors: Bruce
authors: B
authors: Blumberg
authors: University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen, Norway.
authors: Anders
authors: A
authors: Goksøyr
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D019143:Evolution, Molecular; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D000077297:Pregnane X Receptor; D011487:Protein Conformation; D011987:Receptors, Steroid / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014162:Transfection; D001503:Ursidae / Q000235:genetics / Q000378:metabolism*
chemical_list: D004785:Environmental Pollutants; D008024:Ligands; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid
keywords: Environmental pollutants; Human; In vitro ligand activation; Polar bear; Pregnane X receptor