Linked Life Data

17572486

Source:http://linkedlifedata.com/resource/pubmed/id/17572486

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2007-9-10
pubmed:abstractText
The placental trophoblast at different stages of pregnancy contains some drug transporters and xenobiotic-metabolising enzymes, as well as ligand-activated nuclear receptors, which control their inducible transcriptional regulation. Glucocorticoid receptor alpha (GRalpha) is expressed in both placental syncytiotrophoblast and cytotrophoblast. GRalpha was shown to control inducible expression of several enzymes of the cytochrome P-450 family (CYP) and the drug transporter P-glycoprotein in the liver. However, GRalpha-mediated transcriptional regulation of drug transporters and CYPs has not been studied in the placental trophoblast. In this study, we examined the expression and activity of GRalpha in the transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 in placental trophoblast cell lines. Employing RT-PCR, Western blotting, and luciferase gene reporter assay, we detected the expression and activity of GRalpha in JEG3 and BeWo cell lines. However, we observed that only MDR1 mRNA was up-regulated after treatment of placental cells with dexamethasone. Accordingly, only the promoter of the MDR1 gene was activated by dexamethasone in gene reporter assays in placental cells and the activation was abolished by RU486, an antagonist of GRalpha. CYP3A4 and CYP2C9 promoters were activated in placental cells only after co-transfection with hepatocyte nuclear factor 4alpha (HNF4alpha), which indicates the hepatocyte-specific character of GRalpha-mediated regulation of the genes. On the other hand, coexpression of HNF4alpha had no effect on the activation of the MDR1 gene promoter, suggesting HNF4alpha-independent regulation via GRalpha. We conclude that GRalpha may be involved in the transcriptional regulation of P-glycoprotein in the placental trophoblast. We also indicate that the CYP3A4 and CYP2C9 genes are not inducible through GRalpha in placental cell lines, due to the lack of HNF4alpha expression and possibly some additional hepatocyte-specific transcriptional factors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases, http://linkedlifedata.com/resource/pubmed/chemical/CYP2C9 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CYP3A4 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP3A, http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System, http://linkedlifedata.com/resource/pubmed/chemical/Dexamethasone, http://linkedlifedata.com/resource/pubmed/chemical/HNF4A protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Hepatocyte Nuclear Factor 4, http://linkedlifedata.com/resource/pubmed/chemical/P-Glycoprotein, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Glucocorticoid, http://linkedlifedata.com/resource/pubmed/chemical/glucocorticoid receptor alpha
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0143-4004
pubmed:author
pubmed:issnType
Print
pubmed:volume
28
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1004-11
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Examination of Glucocorticoid receptor alpha-mediated transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 genes in placental trophoblast cell lines.
pubmed:affiliation
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskoho 1203, Hradec Kralove 500 05, Czech Republic. petr.pavek@faf.cuni.cz
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't