RT Journal Article
SR Electronic
T1 Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptor AhR
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.112151
DO 10.1124/mol.118.112151
A1 Martina Stepankova
A1 Iveta Bartonkova
A1 Eva Jiskrova
A1 Radim Vrzal
A1 Sridhar Mani
A1 Sandhya Kortagere
A1 Zdenek Dvorak
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/04/06/mol.118.112151.abstract
AB Novel methyl-indoles were identified as endobiotic and xenobiotic ligands of human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhR. 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 AhR were 4-Me-indole (134%), 6-Me-indole (91%) and 7-MeO-indole (80%), respectively. The most effective antagonists of AhR included 3-Me-indole (IC50 19 μM), 2,3-diMe-indole (IC50 11 μM) and 2,3,7-triMe-indole (IC50 12 μM). RT-PCR analyses of CYP1A1 mRNA in LS180 cells confirmed the data from gene reporter assays. Compound leads, 4-Me-indole and 7-MeO-indole, induced substantial nuclear translocation of AhR and enriched binding of AhR to CYP1A1 promoter, as observed using fluorescent immune-histochemistry and chromatin immunoprecipitation assays, respectively. Molecular modeling and docking studies suggest that 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.