Chrysin, baicalein and galangin are indirect activators of the human constitutive androstane receptor (CAR)
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
25625231
DOI
10.1016/j.toxlet.2015.01.013
PII: S0378-4274(15)00025-9
Knihovny.cz E-zdroje
- Klíčová slova
- Constitutive androstane receptor, Cytochrome P450, Flavonoids, Gene regulation, Nuclear receptors,
- MeSH
- buněčné linie MeSH
- cytochrom P450 CYP2B6 metabolismus MeSH
- erbB receptory účinky léků MeSH
- fenobarbital farmakologie MeSH
- flavanony farmakologie MeSH
- flavonoidy farmakologie MeSH
- hepatocyty účinky léků metabolismus MeSH
- konstitutivní androstanový receptor MeSH
- lidé MeSH
- protein Elk-1 s doménou ets účinky léků genetika MeSH
- receptory cytoplazmatické a nukleární agonisté MeSH
- transport proteinů účinky léků MeSH
- vazebná místa účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- baicalein MeSH Prohlížeč
- chrysin MeSH Prohlížeč
- cytochrom P450 CYP2B6 MeSH
- ELK1 protein, human MeSH Prohlížeč
- erbB receptory MeSH
- fenobarbital MeSH
- flavanony MeSH
- flavonoidy MeSH
- galangin MeSH Prohlížeč
- konstitutivní androstanový receptor MeSH
- protein Elk-1 s doménou ets MeSH
- receptory cytoplazmatické a nukleární MeSH
The constitutive androstane receptor (CAR) is a crucial transcriptional regulator of key xenobiotic-metabolizing enzymes such as cytochrome P450 CYP3A4, CYP2C9 and CYP2B6. The flavonoids chrysin, baicalein and galangin have been reported to activate CAR and interfere with EGFR signaling. Nevertheless, it is not known if these flavonoids are direct CAR ligands or indirect phenobarbital-like CAR activators via the inhibition of epidermal growth factor receptor (EGFR) signaling. We analyze the interactions of chrysin, galangin and baicalein and its glycoside baicalin with human CAR. We have employed and validated methods that can study direct interaction with the CAR ligand binding pocket. Secondly, we determined if the compounds affect human EGFR signaling and interact with EGFR. Employing a TR-FRET coactivator assay with recombinant CAR or CAR assembly assay, a consistent activation of CAR with flavonoids and phenobarbital was not observed. It was determined, however, that galangin, chrysin, and baicalein may slightly repress EGFR-Tyr1068 autophosphorylation after EGF treatment, phosphorylation of downstream transcription factor ELK1 and stimulate EGFP-CAR nuclear translocation in primary human hepatocytes. These data suggest that flavonoids chrysin, galangin and baicalein are indirect human CAR activators. This study also demonstrates new approach how to test the direct CAR interaction with its ligands.
Citace poskytuje Crossref.org
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