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.

Department of Cell Biology and Genetics Faculty of Science Palacky University Slechtitelu 27 783 71 Olomouc Czech Republic

Department of Genetics and Department of Medicine Albert Einstein College of Medicine Bronx NY 10461 USA

Department of Medicinal Chemistry College of Pharmacy University of Michigan Ann Arbor MI 48109 1065 USA

Department of Pharmacology University of Colorado School of Medicine Aurora CO 80045 USA

Zobrazit více v PubMed

Denison M.S., Nagy S.R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Ann. Rev. Pharmacol. Toxicol. 2003;43:309–334. doi: 10.1146/annurev.pharmtox.43.100901.135828. PubMed DOI

Angelos M.G., Kaufman D.S. Advances in the role of the aryl hydrocarbon receptor to regulate early hematopoietic development. Curr. Opin. Hematol. 2018;25:273–278. doi: 10.1097/MOH.0000000000000432. PubMed DOI

Bock K.W. From TCDD-mediated toxicity to searches of physiologic AHR functions. Biochem. Pharmacol. 2018;155:419–424. doi: 10.1016/j.bcp.2018.07.032. PubMed DOI

Bock K.W. Aryl hydrocarbon receptor (AHR): From selected human target genes and crosstalk with transcription factors to multiple AHR functions. Biochem. Pharmacol. 2019;168:65–70. doi: 10.1016/j.bcp.2019.06.015. PubMed DOI

Gutierrez-Vazquez C., Quintana F.J. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity. 2018;48:19–33. doi: 10.1016/j.immuni.2017.12.012. PubMed DOI PMC

Fang Z.Z., Krausz K.W., Nagaoka K., Tanaka N., Gowda K., Amin S.G., Perdew G.H., Gonzalez F.J. In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract. Br. J. Pharmacol. 2014;171:1735–1746. doi: 10.1111/bph.12576. PubMed DOI PMC

Safe S., Cheng Y., Jin U.H. The Aryl Hydrocarbon Receptor (AhR) as a Drug Target for Cancer Chemotherapy. Curr. Opin. Toxicol. 2017;2:24–29. doi: 10.1016/j.cotox.2017.01.012. PubMed DOI PMC

Bianchi-Smiraglia A., Bagati A., Fink E.E., Affronti H.C., Lipchick B.C., Moparthy S., Long M.D., Rosario S.R., Lightman S.M., Moparthy K., et al. Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma. J. Clin. Investig. 2018;128:4682–4696. doi: 10.1172/JCI70712. PubMed DOI PMC

Corre S., Tardif N., Mouchet N., Leclair H.M., Boussemart L., Gautron A., Bachelot L., Perrot A., Soshilov A., Rogiers A., et al. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nat. Commun. 2018;9:4775. doi: 10.1038/s41467-018-06951-2. PubMed DOI PMC

Ghotbaddini M., Moultrie V., Powell J.B. Constitutive Aryl Hydrocarbon Receptor Signaling in Prostate Cancer Progression. J. Cancer Treatment Diagn. 2018;2:11–16. PubMed PMC

Darakhshan S., Pour A.B. Tranilast: A review of its therapeutic applications. Pharmacol. Res. 2015;91:15–28. doi: 10.1016/j.phrs.2014.10.009. PubMed DOI

Wilhelm S.M., Rjater R.G., Kale-Pradhan P.B. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev. Clin. Pharmacol. 2013;6:443–451. doi: 10.1586/17512433.2013.811206. PubMed DOI

Stepankova M., Bartonkova I., Jiskrova E., Vrzal R., Mani S., Kortagere S., Dvorak Z. Methylindoles and Methoxyindoles are Agonists and Antagonists of Human Aryl Hydrocarbon Receptor. Mol. Pharmacol. 2018;93:631–644. doi: 10.1124/mol.118.112151. PubMed DOI PMC

Chen I., Safe S., Bjeldanes L. Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem. Pharmacol. 1996;51:1069–1076. doi: 10.1016/0006-2952(96)00060-3. PubMed DOI

Rasmussen M.K., Balaguer P., Ekstrand B., Daujat-Chavanieu M., Gerbal-Chaloin S. Skatole (3-Methylindole) Is a Partial Aryl Hydrocarbon Receptor Agonist and Induces CYP1A1/2 and CYP1B1 Expression in Primary Human Hepatocytes. PLoS ONE. 2016;11:e0154629. doi: 10.1371/journal.pone.0154629. PubMed DOI PMC

Jin U.H., Lee S.O., Sridharan G., Lee K., Davidson L.A., Jayaraman A., Chapkin R.S., Alaniz R., Safe S. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol. Pharmacol. 2014;85:777–788. doi: 10.1124/mol.113.091165. PubMed DOI PMC

Hubbard T.D., Murray I.A., Bisson W.H., Lahoti T.S., Gowda K., Amin S.G., Patterson A.D., Perdew G.H. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 2015;5:12689. doi: 10.1038/srep12689. PubMed DOI PMC

Tfelt-Hansen P., De Vries P., Saxena P.R. Triptans in migraine: A comparative review of pharmacology, pharmacokinetics and efficacy. Drugs. 2000;60:1259–1287. doi: 10.2165/00003495-200060060-00003. PubMed DOI

Cutler N.R., Salazar D.E., Jhee S.S., Fulmor I.E., Ford N., Smith R.A., Sramek J.J. Pharmacokinetics and pharmacodynamics of avitriptan in patients with migraine after oral dosing. Headache. 1998;38:446–452. doi: 10.1046/j.1526-4610.1998.3806446.x. PubMed DOI

John G.W., Perez M., Pauwels P.J., Le Grand B., Verscheure Y., Colpaert F.C. Donitriptan, a unique high-efficacy 5-HT1B/1D agonist: Key features and acute antimigraine potential. CNS Drug Rev. 2000;6:278–289. doi: 10.1111/j.1527-3458.2000.tb00153.x. DOI

Wilt L.A., Nguyen D., Roberts A.G. Insights into the Molecular Mechanism of Triptan Transport by P-glycoprotein. J. Pharm. Sci. 2017;106:1670–1679. doi: 10.1016/j.xphs.2017.02.032. PubMed DOI PMC

Marathe P.H., Greene D.S., Barbhaiya R.H. Disposition of [14C]avitriptan in rats and humans. Drug Metab. Dispos. 1997;25:881–888. PubMed

Marathe P.H., Greene D.S., Kollia G.D., Barbhaiya R.H. A pharmacokinetic interaction study of avitriptan and propranolol. Clin. Pharmacol. Ther. 1998;63:367–378. doi: 10.1016/S0009-9236(98)90168-0. PubMed DOI

Lamas B., Richard M.L., Leducq V., Pham H.P., Michel M.L., Da Costa G., Bridonneau C., Jegou S., Hoffmann T.W., Natividad J.M., et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 2016;22:598–605. doi: 10.1038/nm.4102. PubMed DOI PMC

Zelante T., Iannitti R.G., Cunha C., De Luca A., Giovannini G., Pieraccini G., Zecchi R., D’Angelo C., Massi-Benedetti C., Fallarino F., et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372–385. doi: 10.1016/j.immuni.2013.08.003. PubMed DOI

Denison M.S., Faber S.C. And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses. Curr. Opin. Toxicol. 2017;2:124–131. doi: 10.1016/j.cotox.2017.01.006. PubMed DOI PMC

Tagliabue S.G., Faber S.C., Motta S., Denison M.S., Bonati L. Modeling the binding of diverse ligands within the Ah receptor ligand binding domain. Sci. Rep. 2019;9:10693. doi: 10.1038/s41598-019-47138-z. PubMed DOI PMC

Seok S.H., Lee W., Jiang L., Molugu K., Zheng A., Li Y., Park S., Bradfield C.A., Xing Y. Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex. Proc. Natl. Acad. Sci. USA. 2017;114:5431–5436. doi: 10.1073/pnas.1617035114. PubMed DOI PMC

Goettel J.A., Gandhi R., Kenison J.E., Yeste A., Murugaiyan G., Sambanthamoorthy S., Griffith A.E., Patel B., Shouval D.S., Weiner H.L., et al. AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice. Cell Rep. 2016;17:1318–1329. doi: 10.1016/j.celrep.2016.09.082. PubMed DOI PMC

Saxena P.R., De Vries P., Wang W., Heiligers J.P., MaassenVanDenBrink A., Bax W.A., Yocca F.D. Effects of avitriptan, a new 5-HT 1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential. Naunyn. Schmiedeberg’s Arch. Pharmacol. 1997;355:295–302. doi: 10.1007/PL00004946. PubMed DOI

Meng C.Q. Migraine: Current drug discovery trend. Curr. Med. Chem. 1997;4:385–404.

Marathe P.H., Sandefer E.P., Kollia G.E., Greene D.S., Barbhaiya R.H., Lipper R.A., Page R.C., Doll W.J., Ryo U.Y., Digenis G.A. In vivo evaluation of the absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy. J. Pharmacokinet. Biopharm. 1998;26:1–20. doi: 10.1023/A:1023236823320. PubMed DOI

Sharma A., Jusko W.J., Fulmor I.E., Norton J., Uderman H.D., Salazar D.E. Pharmacokinetics and pharmacodynamics of avitriptan during intravenous administration in healthy subjects. J. Clin. Pharmacol. 1999;39:685–694. doi: 10.1177/00912709922008326. PubMed DOI

Marathe P.H., Greene D.S., Lee J.S., Barbhaiya R.H. Assessment of effect of food, gender, and intra-subject variability in the pharmacokinetics of avitriptan. Biopharm. Drug Dispos. 1998;19:153–157. doi: 10.1002/(SICI)1099-081X(199804)19:3<153::AID-BDD90>3.0.CO;2-T. PubMed DOI

Maier L., Pruteanu M., Kuhn M., Zeller G., Telzerow A., Anderson E.E., Brochado A.R., Fernandez K.C., Dose H., Mori H., et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623–628. doi: 10.1038/nature25979. PubMed DOI PMC

Novotna A., Pavek P., Dvorak Z. Novel stably transfected gene reporter human hepatoma cell line for assessment of aryl hydrocarbon receptor transcriptional activity: Construction and characterization. Environ. Sci. Technol. 2011;45:10133–10139. doi: 10.1021/es2029334. PubMed DOI

Vrzal R., Knoppová B., Bachleda P., Dvořák Z. Effects of oral anorexiant sibutramine on the expression of cytochromes P450s in human hepatocytes and cancer cell lines. J. Biochem. Mol. Toxicol. 2013;27:515–521. doi: 10.1002/jbt.21516. PubMed DOI

Roy A., Kucukural A., Zhang Y. I-TASSER: A unified platform for automated protein structure and function prediction. Nat. Protoc. 2010;5:725–738. doi: 10.1038/nprot.2010.5. PubMed DOI PMC

Trott O., Olson A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010;31:455–461. doi: 10.1002/jcc.21334. PubMed DOI PMC

Soshilov A.A., Denison M.S. Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol. Cell. Biol. 2014;34:1707–1719. doi: 10.1128/MCB.01183-13. PubMed DOI PMC

Motto I., Bordogna A., Soshilov A.A., Denison M.S., Bonati L. New aryl hydrocarbon receptor homology model targeted to improve docking reliability. J. Chem. Inf. Model. 2011;51:2868–2881. doi: 10.1021/ci2001617. PubMed DOI PMC

Laskowski R.A., Swindells M.B. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model. 2011;51:2778–2786. doi: 10.1021/ci200227u. PubMed DOI