Lille-Langøy Roger, Goldstone Jared V, Rusten Marte, Milnes Matthew R, Male Rune, Stegeman John J, Blumberg Bruce, Goksøyr Anders
University of Bergen, Department of Biology, P.O. Box 7803, N-5020 Bergen, Norway.
Woods Hole Oceanographic Institution, 266 Woods Hole Road, 02543-1050 Woods Hole, MA, USA.
Toxicol Appl Pharmacol. 2015 Apr 1;284(1):54-64. doi: 10.1016/j.taap.2015.02.001. Epub 2015 Feb 10.
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.
许多持久性有机污染物（POPs）很容易在北极熊体内蓄积，因为它们是北极食物网中的顶级捕食者。孕烷X受体（PXR，正式名称为NR1I2，本文建议命名为混杂外源性物质受体）是一种外源性物质传感器，直接参与多种环境污染物的代谢途径。
在本研究中，我们使用体外荧光素酶报告基因检测法，比较评估51种选定的药物、农药和新兴污染物激活北极熊和人类PXR的能力。
我们发现，北极熊的PXR被多种测试化合物激活（68%），但其配体特异性比人类PXR略窄，人类PXR被51种测试化合物中的86%激活。所鉴定的大多数激动剂（70%）通过人类PXR对报告基因的诱导作用比对北极熊PXR更强，不过有一些显著的、与环境相关的例外情况。
由于观察到北极熊和人类PXR激活存在差异，每个物种接触环境因子可能会在这两个物种中诱导不同的生物转化。生物信息学分析和结构建模研究表明，不属于配体结合域且不与配体相互作用的氨基酸可以调节受体激活。
