Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptor

Martina Stepankova, Iveta Bartonkova, Eva Jiskrova, Radim Vrzal, Sridhar Mani, Sandhya Kortagere, Zdenek Dvorak

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Novel methylindoles were identified as endobiotic and xenobiotic ligands of the human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhRs. Employing reporter gene assays in AZ-AHR transgenic cells, we determined full agonist, partial agonist, or antagonist activities of tested compounds, having substantially variable EC50, IC50, and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of the AhR were 4-Me-indole (134%), 6-Me-indole (91%), and 7-MeO-indole (80%), respectively. The most effective antagonists of the AhR included 3-Me-indole (IC50; 19 mM), 2,3-diMe-indole (IC50; 11 mM), and 2,3,7-triMe-indole (IC50; 12 mM). Reverse transcription polymerase chain reaction analyses of CYP1A1 mRNA in LS180 cells confirmed the data from gene reporter assays. The compound leads, 4-Me-indole and 7-MeO-indole, induced substantial nuclear translocation of the AhR and enriched binding of the AhR to the CYP1A1 promoter, as observed using fluorescent immunohistochemistry and chromatin immunoprecipitation assays, respectively. Molecular modeling and docking studies suggest the agonists and antagonists likely share the same binding pocket but have unique binding modes that code for their affinity. Binding pocket analysis further revealed that 4-methylindole and 7-methoxyindole can simultaneously bind to the pocket and produce synergistic interactions. Together, these data show a dependence on subtle and specific chemical indole structures as AhR modulators and furthermore underscore the importance of complete evaluation of indole compounds as nuclear receptor ligands.

Original languageEnglish (US)
Pages (from-to)631-644
Number of pages14
JournalMolecular Pharmacology
Issue number6
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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