Indole microbial intestinal metabolites expand the repertoire of ligands and agonists of the human pregnane X receptor
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
33002526
DOI
10.1016/j.toxlet.2020.09.015
PII: S0378-4274(20)30425-2
Knihovny.cz E-zdroje
- Klíčová slova
- Indole metabolites, Intestinal health, Microbial catabolism, Pregnane X receptor,
- MeSH
- cytochrom P-450 CYP3A genetika metabolismus MeSH
- indoly metabolismus MeSH
- kultivované buňky MeSH
- kyseliny indoloctové metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- P-glykoproteiny genetika metabolismus MeSH
- pregnanový X receptor agonisté genetika MeSH
- reportérové geny MeSH
- střevní mikroflóra * MeSH
- střevní sliznice * metabolismus mikrobiologie MeSH
- transfekce MeSH
- tryptofan metabolismus MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ABCB1 protein, human MeSH Prohlížeč
- CYP3A4 protein, human MeSH Prohlížeč
- cytochrom P-450 CYP3A MeSH
- indole MeSH Prohlížeč
- indoleacetamide MeSH Prohlížeč
- indoly MeSH
- kyseliny indoloctové MeSH
- ligandy MeSH
- P-glykoproteiny MeSH
- pregnanový X receptor MeSH
- tryptofan MeSH
The interplays between the metabolic products of intestinal microbiota and the host signaling through xenobiotic receptors, including pregnane X receptor (PXR), are of growing interest, in the context of intestinal health and disease. A distinct class of microbial catabolites is formed from dietary tryptophan, having the indole scaffold in their core structure, which is a biologically active entity. In the current study, we examined a series of ten tryptophan microbial catabolites for their interactions with PXR signaling. Utilizing a reporter gene assay, we identified indole (IND) and indole-3-acetamide (IAD) as PXR agonists. IND and IAD induced PXR-regulated genes CYP3A4 and MDR1 in human intestinal cancer cells. Using time-resolved fluorescence resonance energy transfer, we show that IND (IC50 292 μM) and IAD (IC50 10 μM) are orthosteric ligands of PXR. Binding of PXR in its DNA response elements was enhanced by IND and IAD, as revealed by chromatin immunoprecipitation assay. We demonstrate that tryptophan microbial intestinal metabolites IND and IAD are ligands and agonists of human PXR. These findings are of particular importance in understanding the roles of microbial catabolites in human physiology and pathophysiology. Furthermore, these results are seminal in expanding potential drug repertoire through microbial metabolic mimicry.
Citace poskytuje Crossref.org
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