PMID- 25680588
OWN - NLM
STAT- MEDLINE
DCOM- 20150520
LR  - 20191210
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 284
IP  - 1
DP  - 2015 Apr 1
TI  - Environmental contaminants activate human and polar bear (Ursus maritimus) 
      pregnane X receptors (PXR, NR1I2) differently.
PG  - 54-64
LID - S0041-008X(15)00046-0 [pii]
LID - 10.1016/j.taap.2015.02.001 [doi]
AB  - 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 acids that are not 
      part of the ligand-binding domain and do not interact with the ligand can 
      modulate receptor activation.
CI  - Copyright (c) 2015. Published by Elsevier Inc.
FAU - Lille-Langoy, Roger
AU  - Lille-Langoy R
AD  - University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen, 
      Norway. Electronic address: Roger.lille-langoy@bio.uib.no.
FAU - Goldstone, Jared V
AU  - Goldstone JV
AD  - Woods Hole Oceanographic Institution, 266 Woods Hole Road, 02543-1050 Woods Hole, 
      MA, USA.
FAU - Rusten, Marte
AU  - Rusten M
AD  - University of Bergen, Department of Molecular Biology, P.O. Box 7803, N-5020 
      Bergen, Norway.
FAU - Milnes, Matthew R
AU  - Milnes MR
AD  - Mars Hill University, 100 Athletic Street, Box 6671, Mars Hill, 28754 NC, USA.
FAU - Male, Rune
AU  - Male R
AD  - University of Bergen, Department of Molecular Biology, P.O. Box 7803, N-5020 
      Bergen, Norway.
FAU - Stegeman, John J
AU  - Stegeman JJ
AD  - Woods Hole Oceanographic Institution, 266 Woods Hole Road, 02543-1050 Woods Hole, 
      MA, USA.
FAU - Blumberg, Bruce
AU  - Blumberg B
AD  - University of California, Irvine, 92697 CA, USA.
FAU - Goksoyr, Anders
AU  - Goksoyr A
AD  - University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen, 
      Norway.
LA  - eng
GR  - P42 ES007381/ES/NIEHS NIH HHS/United States
GR  - R21 HD073805/HD/NICHD NIH HHS/United States
GR  - 5P42ES007381/ES/NIEHS NIH HHS/United States
GR  - R21HD073805/HD/NICHD NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150210
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Environmental Pollutants)
RN  - 0 (Ligands)
RN  - 0 (NR1I2 protein, human)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Receptors, Steroid)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Cloning, Molecular
MH  - Dose-Response Relationship, Drug
MH  - Environmental Pollutants/chemistry/*toxicity
MH  - Evolution, Molecular
MH  - Genes, Reporter
MH  - Humans
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Molecular Structure
MH  - Pregnane X Receptor
MH  - Protein Conformation
MH  - Receptors, Steroid/*agonists/chemistry/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Species Specificity
MH  - Structure-Activity Relationship
MH  - Transfection
MH  - Ursidae/genetics/*metabolism
PMC - PMC4387200
MID - NIHMS666589
OTO - NOTNLM
OT  - Environmental pollutants
OT  - Human
OT  - In vitro ligand activation
OT  - Polar bear
OT  - Pregnane X receptor
EDAT- 2015/02/15 06:00
MHDA- 2015/05/21 06:00
PMCR- 2016/04/01
CRDT- 2015/02/15 06:00
PHST- 2014/09/11 00:00 [received]
PHST- 2015/01/16 00:00 [revised]
PHST- 2015/02/02 00:00 [accepted]
PHST- 2015/02/15 06:00 [entrez]
PHST- 2015/02/15 06:00 [pubmed]
PHST- 2015/05/21 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - S0041-008X(15)00046-0 [pii]
AID - 10.1016/j.taap.2015.02.001 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2015 Apr 1;284(1):54-64. doi: 10.1016/j.taap.2015.02.001. 
      Epub 2015 Feb 10.