- MeSH
- beta-buňky fyziologie metabolismus MeSH
- diabetes mellitus 2. typu genetika klasifikace patofyziologie MeSH
- financování organizované MeSH
- glukokinasa fyziologie genetika MeSH
- hepatocytární jaderný faktor 1-alfa fyziologie genetika MeSH
- hepatocytární jaderný faktor 1-beta fyziologie genetika MeSH
- hepatocytární jaderný faktor 4 fyziologie genetika MeSH
- homeoboxové geny fyziologie genetika MeSH
- lidé MeSH
- trans-aktivátory fyziologie genetika MeSH
- Check Tag
- lidé MeSH
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.
- MeSH
- aktivace transkripce fyziologie MeSH
- aromatické hydroxylasy biosyntéza MeSH
- buněčné linie MeSH
- cytochrom P-450 CYP3A MeSH
- dexamethason farmakologie MeSH
- financování organizované MeSH
- hepatocytární jaderný faktor 4 fyziologie MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- nádorové buněčné linie MeSH
- P-glykoprotein biosyntéza MeSH
- promotorové oblasti (genetika) fyziologie MeSH
- receptory glukokortikoidů fyziologie MeSH
- systém (enzymů) cytochromů P-450 biosyntéza MeSH
- těhotenství MeSH
- trofoblasty metabolismus MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
