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Quercetin, Resveratrol, and Curcumin Are Indirect Activators of the Aryl Hydrocarbon Receptor (AHR)
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.ORCID-id: 0000-0003-1045-376X
Visa övriga samt affilieringar
2012 (Engelska)Ingår i: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 25, nr 9, s. 1878-1884Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of the fact that they bind to the receptor with low affinity. The aim of this study was to investigate whether quercetin (QUE), resveratrol (RES), and curcumin (CUR) interfere with the metabolic degradation of the suggested endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) and thereby indirectly activate the AHR. Using recombinant human enzyme, we confirmed earlier reported inhibitory effects of the polyphenols on cytochrome P4501A1 (CYP1A1) activity, and inhibition of metabolic clearance of FICZ was documented in FICZ-treated immortalized human keratinocytes (HaCaT). CYP1A1 activity was induced in HaCaT cells by all three compounds, and when they were added together with FICZ, a prolonged activation was observed after a dose-dependent inhibition period. The same pattern of responses was seen at the transcriptional level as determined with a CYP1A1 reporter assay in human liver hepatoma (HepG2) cells. To test the ability of the polyphenols to activate the AHR in the absence of FICZ, the cells were treated in medium, which in contrast to commercial batches of medium did not contain background levels of FICZ. Importantly, AHR activation was only observed in the commercial medium. Taken together, these findings suggest that QUE, RES, and CUR induce CYP1A1 in an indirect manner by inhibiting the metabolic turnover of FICZ. Humans are exposed to these compounds through the diet and nutritional supplements, and we propose that altered systemic levels of FICZ caused by such compounds may have physiological consequences.

Ort, förlag, år, upplaga, sidor
2012. Vol. 25, nr 9, s. 1878-1884
Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi Farmakologi och toxikologi
Forskningsämne
molekylär biovetenskap
Identifikatorer
URN: urn:nbn:se:su:diva-81821DOI: 10.1021/tx300169eISI: 000308777100009OAI: oai:DiVA.org:su-81821DiVA, id: diva2:565510
Anmärkning

AuthorCount:5;

Tillgänglig från: 2012-11-07 Skapad: 2012-11-01 Senast uppdaterad: 2020-02-06Bibliografiskt granskad
Ingår i avhandling
1. The impact of cytochrome P4501-inhibitors on aryl hydrocarbon receptor signaling
Öppna denna publikation i ny flik eller fönster >>The impact of cytochrome P4501-inhibitors on aryl hydrocarbon receptor signaling
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The aryl hydrocarbon receptor (AHR) best known as a ligand-activated transcription factor that mediates toxic responses to xenobiotics such as dioxins, is also activated by certain endogenous compounds. Activation of the AHR up-regulates transcription of a large number of genes, including those encoding members of the cytochrome P450 1 family of enzymes (CYP1s). Although the AHR has been shown to be involved in several normal processes, its physiological role remains elusive. The endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ), formed from tryptophan, is present in cell culture media and biological specimens. FICZ is an excellent substrate for CYP1 enzymes and together FICZ/AHR/CYP1A1 interactions constitute an auto regulatory feedback loop that controls AHR signaling. A vast number of compounds that inhibit CYP1 enzymes have been reported to be AHR activators, even though they have little or no affinity for the receptor. We hypothesized, that their agonistic effects are dependent on the presence of background levels of FICZ. To test this, AHR signaling in different cell systems exposed to FICZ and/or inhibitors was assessed by measuring EROD activity and CYP1A1 transcription. In addition to a commercial culture medium, a medium free of background levels of FICZ was used. Activation of AHR by of a diverse set of CYP1A1 inhibitors did require FICZ in the culture medium. Furthermore, the compounds tested both prolonged and potentiated FICZ-induced receptor signaling. On the basis of these observations we propose that a compound may activate AHR signaling indirectly by inhibiting CYP1A1 and thereby attenuating the metabolism of FICZ. This mechanism was confirmed for certain polyphenols and pharmaceuticals. Surprisingly, the activating capacity and potentiating effect of two pharmaceuticals on AHR signaling could not be explained by the mechanism proposed, and we speculated that in these cases the agonistic effect might involve interactions of the cellular antioxidant response with the basic transcription machinery. Together, our observations provide a mechanistic explanation as to how compounds that inhibit CYP1A1 can activate AHR signaling. They also indicate that the general perception of the binding pocket of AHR as promiscuous, is probably wrong. The fact that indirect activation of AHR may cause sustained signaling requires further studies in vivo not least, in order to prevent toxicity.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. s. 52
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
molekylär biovetenskap
Identifikatorer
urn:nbn:se:su:diva-128367 (URN)978-91-7649-385-4 (ISBN)
Disputation
2016-05-13, Atrium, Nobels väg 12 B, Karolinska Institutet, Solna, 10:00 (Svenska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Tillgänglig från: 2016-04-20 Skapad: 2016-03-24 Senast uppdaterad: 2020-04-01Bibliografiskt granskad

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Av författaren/redaktören
Bengtsson, JohannaRannug, UlfWincent, Emma
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Institutionen för genetik, mikrobiologi och toxikologi
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Chemical Research in Toxicology
Biomedicinsk laboratorievetenskap/teknologiFarmakologi och toxikologi

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