Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds

Vanessa Delfosse, Béatrice Dendele, Tiphaine Huet, Marina Grimaldi, Abdelhay Boulahtouf, Sabine Gerbal-Chaloin, Bertrand Beucher, Dominique Roecklin, Christina Muller, Roger Rahmani, Vincent Cavaillès, Martine Daujat-Chavanieu, Valérie Vivat, Jean-Marc Pascussi, Patrick Balaguer () and William Bourguet ()
Additional contact information
Vanessa Delfosse: Inserm U1054
Béatrice Dendele: Université de Montpellier
Tiphaine Huet: Inserm U1054
Marina Grimaldi: Université de Montpellier
Abdelhay Boulahtouf: Université de Montpellier
Sabine Gerbal-Chaloin: Université de Montpellier
Bertrand Beucher: Université de Montpellier
Dominique Roecklin: NovAliX
Christina Muller: NovAliX
Roger Rahmani: INRA UMR 1331, TOXALIM
Vincent Cavaillès: Université de Montpellier
Martine Daujat-Chavanieu: Université de Montpellier
Valérie Vivat: NovAliX
Jean-Marc Pascussi: Université de Montpellier
Patrick Balaguer: Université de Montpellier
William Bourguet: Inserm U1054

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9089

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