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 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.
Footnotes
-
This work was supported in part by National Institutes of Health Grant R01 GM60572 and Environmental Protection Agency Grant STAR R-83068601 to B.B., National Institutes of Health Grant R01 GM63666 (to K.E.T.), and National Institutes of Health Grant R01 ES05780 (to. D.L.E.); pilot Grant P30 CA15704 from the University of Washington/Fred Hutchinson Research Center Cancer Research Consortium; and the National Institute of Environmental Health Sciences Center for Ecogenetics and Environmental Health Grant P30 ES07033. Human hepatocytes were obtained through the Liver Tissue Procurement and Distribution System (University of Pittsburgh) funded by National Institutes of Health Contract N01-DK-92310. C.Z. is supported by a University of Washington School of Pharmacy Drug Metabolism, Transporter, and Pharmacogenomics Postdoctoral Fellowship funded by gifts from Abbott, Allergan, Amgen, Bristol-Myers-Squibb, Eli Lilly, Hoffman-La Roche, Johnson and Johnson, Merck, and Pfizer.
-
ABBREVIATIONS: SFN, sulforaphane; GST, glutathione S-transferase; NQO1, NAD(P)H:quinone oxidoreductase-1; UGT, UDP glucuronosyl-transferase; SXR, steroid and xenobiotic receptor; PXR, pregnane X receptor; h, human; RIF, rifampicin; MDR, multidrug resistance; HIV, human immunodeficiency virus; P450, cytochrome P450; MDZ, midazolam; PCN, pregnenolone 16α-carbonitrile; RU486, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one; Wy-14,643, pirinixic acid; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; luc, luciferase; SRC-1, steroid receptor coactivator-1; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; PCR, polymerase chain reaction; MS, mass spectrometry; PPAR, peroxisome proliferator-activated receptor; LBD, ligand binding domain; TIF, transcriptional intermediary factor; ACTR, activator of thyroid and retinoic acid receptor; PBP, proliferator-activated receptor-binding protein; 1′OH-MDZ, 1′-hydoxymidazolam; SR12813, 3,5-di-tert-butyl-4-hydroxystyrene-β,β-diphosphonic acid tetraethyl ester.
-
↵1 Current affiliation: Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10021.
- Received July 25, 2006.
- Accepted October 6, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
