| 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 |
Related Documents
:
|
20627496 - Identification of five partial abc genes in the liver of the antarctic fish trematomus ... 3356336 - Isolation of chicken vitellogenin i and iii cdnas and the developmental regulation of f... 16890166 - Lessons from large-scale gene profiling of the liver in alcoholic liver disease. 16540586 - Involvement of hepatocyte nuclear factor 4alpha in the different expression level betwe... 16541126 - Expression and functional analysis of the rice plasma-membrane intrinsic protein gene f... 12393186 - Multiple signalling pathways mediate insulin-stimulated gene expression in 3t3-l1 adipo... |
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: 2010-11-22 |
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. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: 4-Nitroquinoline 1-oxide forms 8-hydroxydeoxyguanosine in human fibroblasts through reactive oxygen ...
Next Document: Conventional birth weight standards obscure fetal growth restriction in preterm infants.