The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged\nin recent years. We investigated the effects of available antimigraine triptan drugs, having an indole\ncore in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in\nreporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other\ntriptans were very weak or no activators of AhR. Using competitive binding assay and by homology\ndocking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear\ntranslocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by\nimmune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong\ninduction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout,\nimmortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased\nlevels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but\nnot in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak\nligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific\nmanner. Our data warrant the potential off-label therapeutic application of Avitriptan as an\nAhR-agonist drug.
Loading....