The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor

Hongwei Wang, Hao Li, Linda B. Moore, Michael D L Johnson, Jodi M. Maglich, Bryan Goodwin, Olivia R R Ittoop, Bruce Wisely, Katrina Creech, Derek J. Parks, Jon L. Collins, Timothy M. Willson, Ganjam V. Kalpana, Madhukumar Venkatesh, Wen Xie, Sool Y. Cho, John Roboz, Matthew Redinbo, John T. Moore, Sridhar Mani

Research output: Contribution to journalArticle

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Abstract

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 drugdrug interactions.

Original languageEnglish (US)
Pages (from-to)838-857
Number of pages20
JournalMolecular Endocrinology
Volume22
Issue number4
DOIs
StatePublished - Apr 2008

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Coumestrol
Phytoestrogens
Cytoplasmic and Nuclear Receptors
Ligands
Hepatocytes
pregnane X receptor
Cytochrome P-450 CYP3A
Two-Hybrid System Techniques
Xenobiotics
Drug Interactions
Transfection

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor. / Wang, Hongwei; Li, Hao; Moore, Linda B.; Johnson, Michael D L; Maglich, Jodi M.; Goodwin, Bryan; Ittoop, Olivia R R; Wisely, Bruce; Creech, Katrina; Parks, Derek J.; Collins, Jon L.; Willson, Timothy M.; Kalpana, Ganjam V.; Venkatesh, Madhukumar; Xie, Wen; Cho, Sool Y.; Roboz, John; Redinbo, Matthew; Moore, John T.; Mani, Sridhar.

In: Molecular Endocrinology, Vol. 22, No. 4, 04.2008, p. 838-857.

Research output: Contribution to journalArticle

Wang, H, Li, H, Moore, LB, Johnson, MDL, Maglich, JM, Goodwin, B, Ittoop, ORR, Wisely, B, Creech, K, Parks, DJ, Collins, JL, Willson, TM, Kalpana, GV, Venkatesh, M, Xie, W, Cho, SY, Roboz, J, Redinbo, M, Moore, JT & Mani, S 2008, 'The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor', Molecular Endocrinology, vol. 22, no. 4, pp. 838-857. https://doi.org/10.1210/me.2007-0218
Wang, Hongwei ; Li, Hao ; Moore, Linda B. ; Johnson, Michael D L ; Maglich, Jodi M. ; Goodwin, Bryan ; Ittoop, Olivia R R ; Wisely, Bruce ; Creech, Katrina ; Parks, Derek J. ; Collins, Jon L. ; Willson, Timothy M. ; Kalpana, Ganjam V. ; Venkatesh, Madhukumar ; Xie, Wen ; Cho, Sool Y. ; Roboz, John ; Redinbo, Matthew ; Moore, John T. ; Mani, Sridhar. / The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor. In: Molecular Endocrinology. 2008 ; Vol. 22, No. 4. pp. 838-857.
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AU - Venkatesh, Madhukumar

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