Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.
Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.
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DOI：
10.1038/ncomms9089
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发表时间：
2015-09-03
影响因子：
16.6
通讯作者：
Bourguet W
中科院分区：
文献类型：
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作者：
Delfosse V;Dendele B;Huet T;Grimaldi M;Boulahtouf A;Gerbal-Chaloin S;Beucher B;Roecklin D;Muller C;Rahmani R;Cavaillès V;Daujat-Chavanieu M;Vivat V;Pascussi JM;Balaguer P;Bourguet W
人类长期暴露于多种外源性物质，包括环境污染物、药物和饮食成分。这些化合物中有许多被怀疑会影响人类健康，它们在复杂混合物中的组合可能会加剧其有害影响。在这里，我们证明了一种药物雌激素和一种持久性有机氯农药，在单独研究时都表现出较低的功效，但它们协同结合妊娠X受体，导致协同激活。生物物理分析表明，每一种配体都增强了另一种配体的结合亲和力，因此，在每种化学物质单独失活的剂量下，二元混合物会引起实质性的生物反应。高分辨率晶体结构揭示了观察到的协同性的结构基础。我们的研究结果表明，在核受体的配体结合口袋内形成的“超分子配体”有助于化学混合物的协同毒性作用，这可能对内分泌干扰、毒理学和化学风险评估领域具有广泛的意义。干扰内分泌的化学物质作用于核激素受体，如PXR。在这里，Delfosse等人展示了两种这样的化学物质是如何在PXR配体结合口袋中相互作用的，形成了一种所谓的超分子配体，它是一种比单独使用两种化学物质更有效的PXR激活剂。
Humans are chronically exposed to multiple exogenous substances, including environmental pollutants, drugs and dietary components. Many of these compounds are suspected to impact human health, and their combination in complex mixtures could exacerbate their harmful effects. Here we demonstrate that a pharmaceutical oestrogen and a persistent organochlorine pesticide, both exhibiting low efficacy when studied separately, cooperatively bind to the pregnane X receptor, leading to synergistic activation. Biophysical analysis shows that each ligand enhances the binding affinity of the other, so the binary mixture induces a substantial biological response at doses at which each chemical individually is inactive. High-resolution crystal structures reveal the structural basis for the observed cooperativity. Our results suggest that the formation of ‘supramolecular ligands' within the ligand-binding pocket of nuclear receptors contributes to the synergistic toxic effect of chemical mixtures, which may have broad implications for the fields of endocrine disruption, toxicology and chemical risk assessment. Endocrine-disrupting chemicals act on nuclear hormone receptors, such as PXR. Here, Delfosse et al. show how two such chemicals interact with each other in the PXR ligand-binding pocket, forming a so-called supramolecular ligand that is a more potent PXR activator than each of the two chemicals alone.