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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F18%3A73586865" target="_blank" >RIV/61989592:15310/18:73586865 - isvavai.cz</a>

  • Result on the web

    <a href="http://molpharm.aspetjournals.org/content/molpharm/early/2018/04/06/mol.118.112151.full.pdf" target="_blank" >http://molpharm.aspetjournals.org/content/molpharm/early/2018/04/06/mol.118.112151.full.pdf</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1124/mol.118.112151" target="_blank" >10.1124/mol.118.112151</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

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

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    30104 - Pharmacology and pharmacy

Result continuities

  • Project

    Result was created during the realization of more than one project. More information in the Projects tab.

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2018

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Molecular Pharmacology

  • ISSN

    0026-895X

  • e-ISSN

  • Volume of the periodical

    93

  • Issue of the periodical within the volume

    6

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    14

  • Pages from-to

    631-644

  • UT code for WoS article

    000435117100008

  • EID of the result in the Scopus database

    2-s2.0-85052989368