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Title: Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently

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. Objectives: 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 acidsmore » that are not part of the ligand-binding domain and do not interact with the ligand can modulate receptor activation. - Highlights: • Comparative study of ligand activation of human and polar bear PXRs. • Polar bear PXR is a promiscuous ligand-activated nuclear receptor but less so than human PXR. • Environmental contaminants activate human and polar bear PXRs differently. • Expression and ligand promiscuity indicate that PXR is a xenosensor in polar bears.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [3] ;  [2] ;  [5] ;  [1]
  1. University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen (Norway)
  2. Woods Hole Oceanographic Institution, 266 Woods Hole Road, 02543-1050 Woods Hole, MA (United States)
  3. University of Bergen, Department of Molecular Biology, P.O. Box 7803, N-5020 Bergen (Norway)
  4. Mars Hill University, 100 Athletic Street, Box 6671, Mars Hill, 28754 NC (United States)
  5. University of California, Irvine, 92697 CA (United States)
Publication Date:
OSTI Identifier:
22465723
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 284; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMINO ACIDS; ANTIBIOTICS; BEARS; FOOD; GENES; HUMAN POPULATIONS; IN VITRO; LIGANDS; LUCIFERASE; PESTICIDES; POLLUTANTS; RECEPTORS; STEROIDS