Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.
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.
Inserm U1054, Montpellier 34090, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier 34090, France.|Université de Montpellier, Montpellier 34090, France.
Vanessa
V
Delfosse
Université de Montpellier, Montpellier 34090, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34298, France.|Inserm, U1194, Montpellier 34298, France.|ICM, Institut régional du Cancer de Montpellier, Montpellier 34298, France.
Béatrice
B
Dendele
Inserm U1054, Montpellier 34090, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier 34090, France.|Université de Montpellier, Montpellier 34090, France.
Tiphaine
T
Huet
Université de Montpellier, Montpellier 34090, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34298, France.|Inserm, U1194, Montpellier 34298, France.|ICM, Institut régional du Cancer de Montpellier, Montpellier 34298, France.
Marina
M
Grimaldi
Université de Montpellier, Montpellier 34090, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34298, France.|Inserm, U1194, Montpellier 34298, France.|ICM, Institut régional du Cancer de Montpellier, Montpellier 34298, France.
Abdelhay
A
Boulahtouf
Université de Montpellier, Montpellier 34090, France.|Inserm U1040, Montpellier 34295, France.
Sabine
S
Gerbal-Chaloin
Université de Montpellier, Montpellier 34090, France.|Inserm U661, Montpellier 34094, France.|CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier 34094, France.
Bertrand
B
Beucher
NovAliX, Illkirch 67400, France.
Dominique
D
Roecklin
NovAliX, Illkirch 67400, France.
Christina
C
Muller
INRA UMR 1331, TOXALIM, Sophia-Antipolis 06903, France.
Roger
R
Rahmani
Université de Montpellier, Montpellier 34090, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34298, France.|Inserm, U1194, Montpellier 34298, France.|ICM, Institut régional du Cancer de Montpellier, Montpellier 34298, France.
Vincent
V
Cavaillès
Université de Montpellier, Montpellier 34090, France.|Inserm U1040, Montpellier 34295, France.|CHU de Montpellier, Institut de Recherche en Biothérapie, Montpellier 34295, France.
Martine
M
Daujat-Chavanieu
NovAliX, Illkirch 67400, France.
Valérie
V
Vivat
Université de Montpellier, Montpellier 34090, France.|Inserm U661, Montpellier 34094, France.|CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier 34094, France.
Jean-Marc
JM
Pascussi
Université de Montpellier, Montpellier 34090, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier 34298, France.|Inserm, U1194, Montpellier 34298, France.|ICM, Institut régional du Cancer de Montpellier, Montpellier 34298, France.
Patrick
P
Balaguer
Inserm U1054, Montpellier 34090, France.|CNRS UMR5048, Centre de Biochimie Structurale, Montpellier 34090, France.|Université de Montpellier, Montpellier 34090, France.
William
W
Bourguet
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D003460:Crystallization; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000737:chemistry / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000737:chemistry / Q000494:pharmacology*; D005454:Fluorescence Polarization; D056945:Hep G2 Cells; D022781:Hepatocytes; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000494:pharmacology*; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology*; D013058:Mass Spectrometry; D000077297:Pregnane X Receptor; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000737:chemistry / Q000187:drug effects*; D047488:Retinoid X Receptors / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004785:Environmental Pollutants; D004967:Estrogens; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; C001870:nonachlor; D004997:Ethinyl Estradiol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human