Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor That Induces CYP1A1 in Hepatic and Intestinal Cells

Autor: Zdeněk Andrysík, Kristýna Krasulová, Zdenek Dvorak, Aneesh Chandran, Karolína Poulíková, Petra Pečinková, Radim Vrzal, Barbora Vyhlídalová, Sridhar Mani
Rok vydání: 2020
Předmět:
Models
Molecular
Antimigraine drugs
repurposing
Ligands
lcsh:Chemistry
Donitriptan
Basic Helix-Loop-Helix Transcription Factors
Intestinal Mucosa
Promoter Regions
Genetic
lcsh:QH301-705.5
Spectroscopy
Cells
Cultured
Sulfonamides
biology
Chemistry
General Medicine
respiratory system
Tryptamines
Computer Science Applications
Chromatin
Up-Regulation
Molecular Docking Simulation
Organ Specificity
Agonist
medicine.drug_class
Catalysis
Avitriptan
Article
Inorganic Chemistry
medicine
Cytochrome P-450 CYP1A1
Humans
Physical and Theoretical Chemistry
Molecular Biology
Reporter gene
Activator (genetics)
Organic Chemistry
Wild type
Drug Repositioning
Triptans
Aryl hydrocarbon receptor
Molecular biology
respiratory tract diseases
Enzyme Activation
lcsh:Biology (General)
lcsh:QD1-999
Receptors
Aryl Hydrocarbon
biology.protein
Hepatocytes
Aryl Hydrocarbon Receptor
Zdroj: International Journal of Molecular Sciences
Volume 21
Issue 8
International Journal of Molecular Sciences, Vol 21, Iss 2799, p 2799 (2020)
ISSN: 1422-0067
Popis: The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged in recent years. We investigated the effects of available antimigraine triptan drugs, having an indole core in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in reporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other triptans were very weak or no activators of AhR. Using competitive binding assay and by homology docking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear translocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by immune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong induction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout, immortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased levels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but not in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak ligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific manner. Our data warrant the potential off-label therapeutic application of Avitriptan as an AhR-agonist drug.
Databáze: OpenAIRE
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