Roger Lille-Langøy1, Jared V Goldstone2, Marte Rusten3, Matthew R Milnes4, Rune Male3, John J Stegeman2, Bruce Blumberg5, Anders Goksøyr6. 1. University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen, Norway. Electronic address: Roger.lille-langoy@bio.uib.no. 2. Woods Hole Oceanographic Institution, 266 Woods Hole Road, 02543-1050 Woods Hole, MA, USA. 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, USA. 5. University of California, Irvine, 92697 CA, USA. 6. University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen, Norway.
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. 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.
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 bearPXR is activated by a wide range of our test compounds (68%) but has a slightly more narrow ligand specificity than humanPXR 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 humanPXR than via polar bearPXR, 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: Dima Kozakov; David R Hall; Gwo-Yu Chuang; Regina Cencic; Ryan Brenke; Laurie E Grove; Dmitri Beglov; Jerry Pelletier; Adrian Whitty; Sandor Vajda Journal: Proc Natl Acad Sci U S A Date: 2011-08-01 Impact factor: 11.205
Authors: Wen Xie; Mei-Fei Yeuh; Anna Radominska-Pandya; Simrat P S Saini; Yoichi Negishi; Bobbie Sue Bottroff; Geraldine Y Cabrera; Robert H Tukey; Ronald M Evans Journal: Proc Natl Acad Sci U S A Date: 2003-03-18 Impact factor: 11.205
Authors: Andrew M Waterhouse; James B Procter; David M A Martin; Michèle Clamp; Geoffrey J Barton Journal: Bioinformatics Date: 2009-01-16 Impact factor: 6.937
Authors: Robert J Letcher; Wouter A Gebbink; Christian Sonne; Erik W Born; Melissa A McKinney; Rune Dietz Journal: Environ Int Date: 2009-08-15 Impact factor: 9.621
Authors: Roger Lille-Langøy; Odd André Karlsen; Line Merethe Myklebust; Jared V Goldstone; Astrid Mork-Jansson; Rune Male; Bruce Blumberg; John J Stegeman; Anders Goksøyr Journal: Toxicol Sci Date: 2019-03-01 Impact factor: 4.849
Authors: Sabrina Tartu; Roger Lille-Langøy; Trond R Størseth; Sophie Bourgeon; Anders Brunsvik; Jon Aars; Anders Goksøyr; Bjørn Munro Jenssen; Anuschka Polder; Gregory W Thiemann; Vidar Torget; Heli Routti Journal: Sci Rep Date: 2017-11-28 Impact factor: 4.379
Authors: Matthew C Salanga; Nadja R Brun; Rene D Francolini; John J Stegeman; Jared V Goldstone Journal: Toxicol Sci Date: 2020-03-01 Impact factor: 4.849
Authors: Andreas Elentner; Matthias Schmuth; Nikolaos Yannoutsos; Thomas O Eichmann; Robert Gruber; Franz P W Radner; Martin Hermann; Barbara Del Frari; Sandrine Dubrac Journal: J Invest Dermatol Date: 2017-09-18 Impact factor: 8.551