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First published on October 6, 2006; DOI: 10.1124/mol.106.029264

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Received for publication July 26, 2006.
Revised October 6, 2006.
Accepted for publication October 6, 2006.

The dietary isothiocyanate, sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor (SXR)

Changcheng Zhou 1, Emma-Jane Poulton 1, Felix Grun 2, Theo K. Bammler 1, Bruce Blumberg 2, Kenneth E. Thummel 1, David L. Eaton 1*

1 University of Washington 2 University of California, Irvine

* Address correspondence to: E-mail: deaton{at}u.washington.edu

Abstract

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 anticancer 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 pro-toxicants, pharmaceutical compounds and endogenous sterols. Among the most important mediators of CYP3A4 expression is the nuclear hormone receptor, steroid and xenobiotic receptor (SXR). 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 (MDZ) clearance in human primary hepatocytes. Thus, SFN is the first identified naturally occurring antagonist for SXR. 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.


Key words: Sex hormones, Transcriptional coactivators, MDR/p-Glycoprotein, Cytochrome P450, Regulation - transcriptional, Oxidative stress/antioxidants, Toxicant-induced gene express, Resistance


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