Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F23%3A00583492" target="_blank" >RIV/68081707:_____/23:00583492 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15310/23:73620337

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S037842742301055X?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S037842742301055X?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.toxlet.2023.09.012" target="_blank" >10.1016/j.toxlet.2023.09.012</a>

Result language

angličtina

Original language name

Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines

Original language description

Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30108 - Toxicology

Project

<a href="/en/project/GA22-00355S" target="_blank" >GA22-00355S: Pharmacological mimicry of microbial metabolites in the modulation of intestinal health</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

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

Name of the periodical

Toxicology Letters

ISSN

0378-4274

e-ISSN

1879-3169

Volume of the periodical

387

Issue of the periodical within the volume

SEP 15 2023

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

13

Pages from-to

63-75

UT code for WoS article

001088110700001

EID of the result in the Scopus database

2-s2.0-85172921204