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The Phytoestrogen Coumestrol Is a Naturally Occurring Antagonist of the Human Pregnane X Receptor

Albert Einstein College of Medicine, Albert Einstein Cancer Center (H.W., H.L., S.M.), Departments of Medicine (H.W., H.L., S.M.) and Molecular Genetics (G.V.K., M.V.), Bronx, New York 10461; Molecular Discovery Research (L.B.M., J.M.M., B.G., O.R.R.I., B.W., K.C., D.J.P., J.L.C., T.M.W., J.T.M.), GlaxoSmithKline, Research Triangle Park, North Carolina 27709; University of North Carolina (M.D.L.J., M.R.), Chapel Hill, North Carolina 27599; University of Pittsburgh (W.X.), Pittsburgh, Pennsylvania 15261; and Mount Sinai School of Medicine (S.Y.C., J.R.), New York, New York 10029

Address all correspondence and requests for reprints to: Sridhar Mani, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: smani{at}montefiore.org.

Antagonizing the action of the human nuclear xenobiotic receptor pregnane X receptor (PXR) may have important clinical implications in preventing drug-drug interactions and improving therapeutic efficacy. We provide evidence that a naturally occurring phytoestrogen, coumestrol, is an antagonist of the nuclear receptor PXR (NR1I2). In transient transfection assays, coumestrol was able to suppress the agonist effects of SR12813 on human PXR activity. PXR activity was assessed and correlated with effects on the metabolism of the anesthetic tribromoethanol and on gene expression in primary human hepatocytes. We found that coumestrol was able to suppress the effects of PXR agonists on the expression of the known PXR target genes, CYP3A4 and CYP2B6, in primary human hepatocytes as well as inhibit metabolism of tribromoethanol in humanized PXR mice. Coumestrol at concentrations above 1.0 µM competed in scintillation proximity assays with a labeled PXR agonist for binding to the ligand-binding cavity. However, mammalian two-hybrid assays and transient transcription data using ligand-binding-cavity mutant forms of PXR show that coumestrol also antagonizes coregulator recruitment. This effect is likely by binding to a surface outside the ligand-binding pocket. Taken together, these data imply that there are antagonist binding site(s) for coumestrol on the surface of PXR. These studies provide the basis for development of novel small molecule inhibitors of PXR with the ultimate goal of clinical applications toward preventing drug-drug interactions.

NURSA Molecule Pages Link:

Nuclear Receptors:   PXR  |  CAR  |  ERα  |  ERβ

Coregulators:   SRC-1

Ligands:   Pregnenolone carbonitrile  |  T0901317  |  17β-Estradiol  |  SR12813