Chrysin, baicalein and galangin are indirect activators of the human constitutive androstane receptor (CAR)
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25625231
DOI
10.1016/j.toxlet.2015.01.013
PII: S0378-4274(15)00025-9
Knihovny.cz E-resources
- Keywords
- Constitutive androstane receptor, Cytochrome P450, Flavonoids, Gene regulation, Nuclear receptors,
- MeSH
- Cell Line MeSH
- Cytochrome P-450 CYP2B6 metabolism MeSH
- ErbB Receptors drug effects MeSH
- Phenobarbital pharmacology MeSH
- Flavanones pharmacology MeSH
- Flavonoids pharmacology MeSH
- Hepatocytes drug effects metabolism MeSH
- Constitutive Androstane Receptor MeSH
- Humans MeSH
- ets-Domain Protein Elk-1 drug effects genetics MeSH
- Receptors, Cytoplasmic and Nuclear agonists MeSH
- Protein Transport drug effects MeSH
- Binding Sites drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- baicalein MeSH Browser
- chrysin MeSH Browser
- Cytochrome P-450 CYP2B6 MeSH
- ELK1 protein, human MeSH Browser
- ErbB Receptors MeSH
- Phenobarbital MeSH
- Flavanones MeSH
- Flavonoids MeSH
- galangin MeSH Browser
- Constitutive Androstane Receptor MeSH
- ets-Domain Protein Elk-1 MeSH
- Receptors, Cytoplasmic and Nuclear 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.
References provided by Crossref.org
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