QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.029264v1 71/1/220    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, C. Articles by Eaton, D. L. Search for Related Content PubMed PubMed Citation Articles by Zhou, C. Articles by Eaton, D. L.

The Dietary Isothiocyanate Sulforaphane Is an Antagonist of the Human Steroid and Xenobiotic Nuclear Receptor

Departments of Pharmaceutics (C.Z., K.E.T.) and Environmental and Occupational Health Sciences (E.-J.P., T.K.B., D.L.E.), University of Washington, Seattle, Washington; and Department of Developmental and Cell Biology, University of California, Irvine, California (F.G., B.B.)

Sulforaphane (SFN) is a biologically active phytochemical found abundantly in broccoli. SFN has been promoted as a putative chemopreventive agent to reduce cancer, and most studies have associated its anti-cancer effects with the induction of phase II xenobiotic metabolism enzymes via activation of the Keap1/Nrf2 antioxidant response pathway. Interestingly, SFN can significantly down-regulate cytochrome P450 3A4 (CYP3A4) expression in human primary hepatocytes. CYP3A4 is responsible for the hepatic and intestinal metabolism of numerous protoxicants, pharmaceutical compounds, and endogenous sterols. Among the most important mediators of CYP3A4 expression is the nuclear hormone receptor, steroid and xenobiotic receptor (SXR; also called "hPXR"). SXR functions as a xenobiotic sensor to coordinately regulate xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. Here, we report that SFN is a specific antagonist of human SXR and that it inhibits SXR-mediated induction of drug clearance. SFN can bind directly to SXR, inhibit SXR coactivator recruitment, and efficiently repress SXR activities. Furthermore, SFN inhibited SXR-mediated CYP3A4 expression and CYP3A4-catalyzed midazolam clearance in human primary hepatocytes. Thus, SFN is the first identified naturally occurring antagonist for SXR (hPXR). Because induction of CYP3A4 can result in adverse drug responses (e.g., lack of efficacy), which are a major public health problem, this discovery could lead to the development of important new therapeutic and dietary approaches to reduce the frequency of undesirable inducer-drug interactions.

Address correspondence to: Dr. David L. Eaton, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195. E-mail: deaton{at}u.washington.edu

This article has been cited by other articles:

				L. Li, T. Chen, J. D. Stanton, T. Sueyoshi, M. Negishi, and H. Wang The Peripheral Benzodiazepine Receptor Ligand 1-(2-Chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide Is a Novel Antagonist of Human Constitutive Androstane Receptor Mol. Pharmacol., August 1, 2008; 74(2): 443 - 453. [Abstract] [Full Text] [PDF]

				H. Wang, H. Li, L. B. Moore, M. D. L. Johnson, J. M. Maglich, B. Goodwin, O. R. R. Ittoop, B. Wisely, K. Creech, D. J. Parks, et al. The Phytoestrogen Coumestrol Is a Naturally Occurring Antagonist of the Human Pregnane X Receptor Mol. Endocrinol., April 1, 2008; 22(4): 838 - 857. [Abstract] [Full Text] [PDF]

				C. Healan-Greenberg, J. F. Waring, D. J. Kempf, E. A. G. Blomme, R. G. Tirona, and R. B. Kim A Human Immunodeficiency Virus Protease Inhibitor Is a Novel Functional Inhibitor of Human Pregnane X Receptor Drug Metab. Dispos., March 1, 2008; 36(3): 500 - 507. [Abstract] [Full Text] [PDF]

				Y. Chen, Y. Tang, M.-T. Wang, S. Zeng, and D. Nie Human Pregnane X Receptor and Resistance to Chemotherapy in Prostate Cancer Cancer Res., November 1, 2007; 67(21): 10361 - 10367. [Abstract] [Full Text] [PDF]

				G. Lemaire, C. Benod, V. Nahoum, A. Pillon, A.-M. Boussioux, J.-F. Guichou, G. Subra, J.-M. Pascussi, W. Bourguet, A. Chavanieu, et al. Discovery of a Highly Active Ligand of Human Pregnane X Receptor: A Case Study from Pharmacophore Modeling and Virtual Screening to "In Vivo" Biological Activity Mol. Pharmacol., September 1, 2007; 72(3): 572 - 581. [Abstract] [Full Text] [PDF]

				S. Ekins, C. Chang, S. Mani, M. D. Krasowski, E. J. Reschly, M. Iyer, V. Kholodovych, N. Ai, W. J. Welsh, M. Sinz, et al. Human Pregnane X Receptor Antagonists and Agonists Define Molecular Requirements for Different Binding Sites Mol. Pharmacol., September 1, 2007; 72(3): 592 - 603. [Abstract] [Full Text] [PDF]