(‐)‐Epicatechin Activates Pregnane X Receptor (PXR) in Skeletal Muscle

Abstract

(‐)‐Epicatechin (EC) is a flavanol that has shown numerous biological effects such as: decrease cardiovascular dysfunction risk, metabolism regulation, induction of skeletal muscle (SkM) cells differentiation among others. The EC‐induced effects involve its interaction with acceptor/receptor like molecules and seem to be specific. The described EC acceptor/receptor molecules do not explain at all the EC’s effect on SkM. Based on structural similitude between EC and steroidal backbone, we decided to search for proteins that can recognize/interact with steroids and which activation/deactivation leads to similar effects as those induced by EC. The pregnane X receptor (PXR) can fulfill those characteristics; although the main function of this receptor is xenobiotics depuration, it is also linked to metabolism regulation and cell proliferation due to its transcription factor function. Taking as main objective the evaluation of a possible EC‐PXR interaction, docking assays were performed in order to establish if affinity exist between both molecules and if the interaction is comparable with a known agonist: pregnenolone‐16‐carbonitrile (PCN). To confirm the affinity of EC from PXR, this receptor was isolated from rat’s skeletal muscle homogenate using affinity chromatography with a column which has the flavanol attached. Similarly, the activation of PXR by (‐)‐Epicatechin was evaluated in vitro; cultured C2C12 cells (mouse myoblast) were stimulated with 0.1μM of EC or 0.1μM of PCN in order to see the expression of Cyp3a11 (a downstream gene promoted by PXR); the effect was blocked with 1μM of the antagonist Ketoconazole. The results reported here demonstrated that (‐)‐Epicatechin could interact and activate PXR.Support or Funding InformationConacyt 253769