The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor.

The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Research Abstract Details 

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The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Abstract Text:

Changcheng Zhou,Emma-Jane Poulton,Felix ,Theo K Bammler,Bruce Blumberg,Kenneth E Thummel,David L Eaton,

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.

The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Publishing Authors By Initials

C Zhou,EJ Poulton,F ,TK Bammler,B Blumberg,KE Thummel,DL Eaton,

For similar organic chemicals: cyanates: thiocyanates research abstracts see: organic chemicals: cyanates: thiocyanates research

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The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular pharmacology

VOLUME: 71

Page Numbers: 220-9

Journal Abbreviation: Mol. Pharmacol.

ISSN: 0026-895X

DAY: 6

MONTH: 10

YEAR: 2006

The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 35623

The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Keywords Mesh Terms:

KEYWORDS: Thiocyanates

MESH TERMS: pharmacology

Chemical & Substance for Abstract: The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Information

Substance Name: CYP3A4 protein, human

Registry Number: EC 1.14.13.67

Grant and Affiliation Information for The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor.

AFFILIATION: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: R01-GM60572

ACRONYM: GM

MEDLINETA: Mol Pharmacol

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