Interspecies Differences in Activation of Peroxisome Proliferator-Activated Receptor γ by Pharmaceutical and Environmental Chemicals.

Endocrine disrupting chemicals (EDCs) are able to deregulate the hormone system, notably through interactions with nuclear receptors (NRs). The mechanisms of action and biological effects of many EDCs have mainly been tested on human and mouse but other species such as zebrafish and xenopus are increasingly used as a model to study the effects of EDCs. Among NRs, peroxisome proliferator-activated receptor γ (PPARγ) is a main target of EDCs, for which most experimental data have been obtained from human and mouse models.

Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines.

To characterize human nuclear receptor (NR) specificity of synthetic pharmaceutical chemicals we established stable cell lines expressing the ligand binding domains (LBDs) of human FXR, LXRα, LXRβ, CAR, and RORγ fused to the yeast GAL4 DNA binding domain (DBD). As we have already done for human PXR, a two-step transfection procedure was used. HeLa cells stably expressing a Gal4 responsive gene (HG5LN cell line) were transfected by Gal4-NRs expressing plasmids.

The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor.

The human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous compounds and plays a critical role in the control of detoxifying enzymes and transporters regulating liver and gastrointestinal drug metabolism and clearance. hPXR is also involved in both the development of multidrug resistance and enhanced cancer cells aggressiveness. Moreover, its unintentional activation by pharmaceutical drugs can mediate drug-drug interactions and cause severe adverse events.

Targeting the pregnane X receptor using microbial metabolite mimicry.

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space.

Nuclear receptors are the major targets of endocrine disrupting chemicals.

Endocrine disrupting chemicals (EDCs) are exogenous substances that are suspected to cause adverse effects in the endocrine system mainly by acting through their interaction with nuclear receptors such as the estrogen receptors α and β (ERα and ERβ), the androgen receptor (AR), the pregnan X receptor (PXR), the peroxisome proliferator activated receptors α and γ (PPARα, PPARγ) and the thyroid receptors α and β (TRα and TRβ). More recently, the retinoid X receptors (RXRα, RXRβ and RXRγ), the constitutive androstane receptor (CAR) and the estrogen related receptor γ (ERRγ) have also been identified as targets of EDCs. Finally, nuclear receptors still poorly studied for their interaction with environmental ligands such as the progesterone receptor (PR), the mineralocorticoid receptor (MR), the glucocorticoid receptor (GR), the retinoic acid receptors (RAR α, RARβ and RARγ), the farnesoid X receptor (FXR) and the liver X receptors α and β (LXRα and LXβ) as well are suspected targets of EDCs.