Document Detail


The mycoestrogen zearalenone induces CYP3A through activation of the pregnane X receptor.
MedLine Citation:
PMID:  16547076     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 microM. 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.
Authors:
Xunshan Ding; Kristin Lichti; Jeff L Staudinger
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-03-17
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  91     ISSN:  1096-6080     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-18     Completed Date:  2006-08-09     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  448-55     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Animals
Cell Line, Transformed
Cell Line, Tumor
Cells, Cultured
Cytochrome P-450 CYP3A / biosynthesis
Cytochrome P-450 Enzyme System / biosynthesis
Estrogen Receptor alpha / metabolism
Estrogens, Non-Steroidal / toxicity*
Hepatocytes / drug effects*,  metabolism
Humans
Membrane Proteins / biosynthesis
Mice
Mice, Knockout
Models, Animal
Receptors, Cytoplasmic and Nuclear / deficiency,  genetics,  metabolism*
Receptors, Steroid / deficiency,  genetics,  metabolism*
Transduction, Genetic
Zearalenone / toxicity*
Grant Support
ID/Acronym/Agency:
1R01DK068443-01A1/DK/NIDDK NIH HHS; R01 DK068443-01A1/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Estrogen Receptor alpha; 0/Estrogens, Non-Steroidal; 0/Membrane Proteins; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, Steroid; 0/pregnane X receptor; 17924-92-4/Zearalenone; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cyp3a11 protein, mouse; EC 1.14.14.1/Cytochrome P-450 CYP3A
Comments/Corrections

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