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ToxSci Advance Access originally published online on March 17, 2006
Toxicological Sciences 2006 91(2):448-455; doi:10.1093/toxsci/kfj163
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Mycoestrogen Zearalenone Induces CYP3A through Activation of the Pregnane X Receptor

Xunshan Ding, Kristin Lichti and Jeff L. Staudinger1

Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045

Received January 31, 2006; accepted March 2, 2006

Zearalenone is a mycoestrogen that is produced in the fungi Fusarium graminearum, Fusarium culmorum, Fusarium equiseti, and Fusarium crookwellense. These fungi commonly exist in agricultural products. Human pregnane X receptor (hPXR) is a ligand-activated transcription factor that regulates the expression of numerous hepatic drug-metabolizing enzymes, including several clinically important cytochrome P450s. In this report, we show that zearalenone is an efficacious ligand for hPXR. We also describe the creation and validation of a novel adenoviral-mediated transduction protocol used to express functional FLAG-tagged-hPXR protein in a transformed cell line (HepG2) and primary cell types (cultured hepatocytes). Treatment of hPXR-transduced HepG2 cells with zearalenone induces expression of CYP3A4, the "prototypical" PXR-target gene in human liver. Treatment of hPXR-transduced cultured hepatocytes isolated from PXR-knockout mice with zearalenone induces the expression of Cyp3a11, the prototypical murine hepatic PXR-target gene. Using mammalian two-hybrid assays, we show that zearalenone displaces the nuclear receptor corepressor protein N-CoR from hPXR, while it recruits coactivator proteins steroid receptor coactivator-1, Glucocorticoid Receptor-Interacting Protein 1 and PPAR-Binding protein (GRIP1) and PBP to hPXR. Concentration-response analysis using a PXR-responsive reporter gene assay reveals that zearalenone activates hPXR with an EC50 value of approximately 1.5 µM. Because activation of hPXR represents the molecular basis of an important class of drug interactions, our findings suggest that studies to investigate the potential of zearalenone to induce the metabolism of other drugs in humans are warranted. In addition, due to the limited availability of primary human hepatocytes, our adenoviral-mediated hPXR expression protocol will likely prove useful in studies of the xenobiotic response.

Key Words: PXR; CYP3A; zearalenone; drug interaction; cofactor; nuclear receptor.


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