Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently
Goldstone, Jared V.
Milnes, Matthew R.
Stegeman, John J.
MetadataShow full item record
KeywordIn vitro ligand activation; Pregnane X receptor; Polar bear; Human; Environmental pollutants
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. 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. 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. 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.
© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Toxicology and Applied Pharmacology 284 (2015): 54-64, doi:10.1016/j.taap.2015.02.001.
Suggested CitationArticle: Lille-Langoy, Roger, Goldstone, Jared V., Rusten, Marte, Milnes, Matthew R., Male, Rune, Stegeman, John J., Blumberg, Bruce, Goksoyra, Anders, "Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently", Toxicology and Applied Pharmacology 284 (2015): 54-64, DOI:10.1016/j.taap.2015.02.001, https://hdl.handle.net/1912/7189
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International
Showing items related by title, author, creator and subject.
Expression and reconstitution of the bioluminescent Ca2+ reporter aequorin in human embryonic stem cells, and exploration of the presence of functional IP3 and ryanodine receptors during the early stages of their differentiation into cardiomyocytes Chan, Harvey Y. S.; Cheung, Man Chun; Gao, Yi; Miller, Andrew L.; Webb, Sarah E. (Springer, 2016-07-19)In order to develop a novel method of visualizing possible Ca2+ signaling during the early differentiation of hESCs into cardiomyocytes and avoid some of the inherent problems associated with using fluorescent reporters, ...
Modeling the influence of environmental factors on human respiratory irritation from natural exposures to Karenia brevis aerosols Kirkpatrick, Gary; Kirkpatrick, Barbara; Hitchcock, Gary; Hoagland, Porter (2015-11-11)The Coupled Natural and Human Systems program of US National Science Foundation is supporting our effort to elucidate linkages between harmful algal blooms and associated impacts on human health, society and economy of ...
Environmental controls, oceanography and population dynamics of pathogens and harmful algal blooms: connecting sources to human exposure Dyble, Julianne; Bienfang, Paul; Dusek, Eva; Hitchcock, Gary; Holland, A. Fredrick; Laws, Edward A.; Lerczak, James A.; McGillicuddy, Dennis J.; Minnett, Peter; Moore, Stephanie K.; O'Kelly, Charles; Solo-Gabriele, Helena M.; Wang, John D. (BioMed Central, 2008-11-07)Coupled physical-biological models are capable of linking the complex interactions between environmental factors and physical hydrodynamics to simulate the growth, toxicity and transport of infectious pathogens and harmful ...