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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

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

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Molecular Pharmacology

ISSN

0026-895X

e-ISSN

—

Svazek periodika

93

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

631-644

Kód UT WoS článku

000435117100008

EID výsledku v databázi Scopus

2-s2.0-85052989368