Journal article
Methylindoles and Methoxyindoles are Agonists and Antagonists of Human Aryl Hydrocarbon Receptor
Molecular pharmacology, v 93(6), pp 631-644
01 Jun 2018
PMID: 29626056
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 (E-MAX 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 mu M), 2,3-diMe-indole (IC50; 11 mu M), and 2,3,7-triMe-indole (IC50; 12 mu M). 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.
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Details
- Title
- Methylindoles and Methoxyindoles are Agonists and Antagonists of Human Aryl Hydrocarbon Receptor
- Creators
- Martina Stepankova - Drexel UniversityIveta Bartonkova - Drexel UniversityEva Jiskrova - Drexel UniversityRadim Vrzal - Drexel UniversitySridhar Mani - Albert Einstein College of MedicineSandhya Kortagere - Drexel UniversityZdenek Dvorak - Palacký University, Olomouc
- Publication Details
- Molecular pharmacology, v 93(6), pp 631-644
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 14
- Grant note
- 362520 / Broad Medical Research Program at Crohn's & Colitis Foundation of America CA127231; CA161879 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30DK041296 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) PR160167; R43DK105694; P30DK041296 / Department of Defence Partnering PI P30CA013330 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) PrF-2017-004; PrF-2018-005 / Palacky University in Olomouc P30 DK020541 / National Institutes of Health Diabetes Research Center CZ.02.1.01/0.0/0.0/16_019/0000754 / Operational Programme Research, Development and Education, European Regional Development Fund, Ministry of Education, Youth and Sports of the Czech Republic Institute for Clinical and Translational Research Pilot Award [AECOM] P303/12/G163 / Czech Science Foundation; Grant Agency of the Czech Republic P30 CA013330 / National Institutes of Health Cancer Center; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000435117100008
- Scopus ID
- 2-s2.0-85052989368
- Other Identifier
- 991019167988304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy