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

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 coop

SUBMITTER: Delfosse V 

PROVIDER: S-EPMC4569708 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature