Abstract
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.
Highlights
The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the family of basic helix-loop-helix transcription factors
Employing the methods of RT-PCR, western blotting, reporter-gene assays, Chromatin Immunoprecipitation (ChIP)-assay, radio-ligand binding assay, protein immune-precipitation, in situ immune-fluorescence and in silico docking, we demonstrate that Avitriptan is a weak ligand and agonist of AhR that induces the expression of the AhR-target genes
We examined the effects of antimigraine drugs of triptan class on AhR-CYP1A1 signaling in human in vitro cell models
Summary
The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the family of basic helix-loop-helix transcription factors. The attempts for therapeutic and preventive targeting of AhR have emerged in recent years [6]. Both natural and synthetic AhR agonists and antagonists are potential drug candidates. The AhR active drugs, such as tranilast, flutamide or omeprazole, might be effective chemotherapeutics for the treatment of breast and pancreatic cancers [7]. The manifold of indole-based compounds were demonstrated as ligands of AhR, including synthetic xenobiotic indoles (e.g., methylindoles and methoxyindoles) [13], dietary indoles (e.g., indole-3-carbinol and diindolylmethane) [14] and microbial catabolites of tryptophan, such as skatole [15], tryptamine, indole-3-acetate [16] and indole [17]
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