| Added by | mollevi |
|---|---|
| Last modified by | ircm doc |
| Group name | EquipeVC |
| Item Type | Journal Article |
| Title | Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds |
| Creator | Delfosse et al. |
| Author | V. Delfosse |
| Author | B. Dendele |
| Author | T. Huet |
| Author | M. Grimaldi |
| Author | A. Boulahtouf |
| Author | S. Gerbal-Chaloin |
| Author | B. Beucher |
| Author | D. Roecklin |
| Author | C. Muller |
| Author | R. Rahmani |
| Author | V. Cavailles |
| Author | M. Daujat-Chavanieu |
| Author | V. Vivat |
| Author | J. M. Pascussi |
| Author | P. Balaguer |
| Author | W. Bourguet |
| 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. |
| Publication | Nat Commun |
| Volume | 6 |
| Pages | 8089 |
| Date | 2015 |
| Journal Abbr | Nature communications |
| DOI | 10.1038/ncomms9089 |
| ISSN | 2041-1723 (Electronic) 2041-1723 (Linking) |
| Tags | original, own |
| Date Added | 2018/11/14 - 12:10:52 |
| Date Modified | 2025/01/09 - 15:26:52 |
| Notes and Attachments | (Note) (Note) 26333997 (Attachment) |
Institut de Recherche en Cancérologie de
