MI-883 is a potent, dual acting constitutive androstane receptor (CAR) agonist/pregnane X receptor (PXR) antagonist with EC50 of 73 nM in TR-FRET CAR coactivation assays, competes with fluorophore binding to recombinant PXR LBD with IC50 of 0.1 uM.
MI-883 significantly stimulates CAR LBD assembly (EC50=0.38 uM), CAR3 variant activationand the translocation of EGFR-CAR+A hybrid protein into nucleus, which is an initial step of CAR activation.
MI-883 significantly upregulates CYP2B6 mRNA in HepaRG and primary human hepatocytes (PHH), but not in HepaRG KO CAR cells with ablated CAR expression.
MI-883 significantly suppresses both basal and rifampicin-induced PXR activation in HepG2 cells with IC50 of 2.03 uM and 3.60 uM respectively in transient transfection luciferase reporter assays.
MI-883 induces significant CYP3A4 mRNA downregulation, pER6-luc luciferase construct inhibition below the control (basal) expression, and significant suppression of PXR ligand activity in LS174T cells.
MI-883 effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation.
MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets.