Linked Life Data

17998298

Source:http://linkedlifedata.com/resource/pubmed/id/17998298

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2008-1-25
pubmed:abstractText
Azole antifungal drug ketoconazole has recently been demonstrated as an inhibitor of a ligand-induced pregnane X receptor (PXR)-mediated transcriptional regulation of the CYP3A4 gene through disruption of PXR interaction with steroid receptor coactivator (SRC)-1. In contrast, other clotrimazole-derived antifungal agents are known as potent inducers of CYP3A4 through PXR. In the present study, we examined effects of azole antimycotics clotrimazole, ketoconazole, econazole, oxiconazole, miconazole, fluconazole, and itraconazole on PXR-mediated expression of CYP3A4. We investigated individual effects of the tested azoles as well as their action on rifampicin-induced PXR-mediated transactivation and expression of CYP3A4 in LS174T cell line and primary human hepatocytes, their interactions with PXR ligand-binding domain, and azole-mediated recruitment of SRC-1 to PXR. In addition, applying the pharmacodynamic approach and dose-response analysis, we aimed to describe the nature of potential interactions of tested azole antimycotics coadministered with a prototypical PXR ligand rifampicin in transactivation of CYP3A4 gene. We describe additive and antagonistic interactions of partial and full agonists of PXR nuclear receptor in the therapeutic group of azole antimycotics in rifampicin-mediated transactivation of CYP3A4. We show that oxiconazole is a highly efficacious activator of CYP3A4 transactivation, which could be antagonized by rifampicin in a competitive manner. In addition, we show that activation of the CYP3A4 promoter is a complex process, which is not exclusively determined by azole-PXR interactions, and we suggest that the ability of some azoles to affect recruitment of SRC-1 to PXR modulates their net effects in transactivation of CYP3A4 both in the absence or presence of rifampicin.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1521-009X
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
36
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
339-48
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:17998298-Aged, pubmed-meshheading:17998298-Animals, pubmed-meshheading:17998298-Antifungal Agents, pubmed-meshheading:17998298-Azoles, pubmed-meshheading:17998298-Cell Line, pubmed-meshheading:17998298-Cell Line, Tumor, pubmed-meshheading:17998298-Cells, Cultured, pubmed-meshheading:17998298-Cercopithecus aethiops, pubmed-meshheading:17998298-Cytochrome P-450 CYP3A, pubmed-meshheading:17998298-Cytochrome P-450 Enzyme System, pubmed-meshheading:17998298-Female, pubmed-meshheading:17998298-Gene Expression, pubmed-meshheading:17998298-Genes, Reporter, pubmed-meshheading:17998298-Hepatocytes, pubmed-meshheading:17998298-Humans, pubmed-meshheading:17998298-Male, pubmed-meshheading:17998298-Middle Aged, pubmed-meshheading:17998298-Promoter Regions, Genetic, pubmed-meshheading:17998298-RNA, Messenger, pubmed-meshheading:17998298-Receptors, Steroid, pubmed-meshheading:17998298-Rifampin, pubmed-meshheading:17998298-Transfection
pubmed:year
2008
pubmed:articleTitle
Azole antimycotics differentially affect rifampicin-induced pregnane X receptor-mediated CYP3A4 gene expression.
pubmed:affiliation
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't