title: Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR).
abstract: 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.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Afshin
authors.initials: A
authors.lastname: Mohammadi-Bardbori
authors.forename: Johanna
authors.initials: J
authors.lastname: Bengtsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Rannug
authors.forename: Agneta
authors.initials: A
authors.lastname: Rannug
authors.forename: Emma
authors.initials: E
authors.lastname: Wincent
mesh_terms: D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003474:Curcumin / Q000737:chemistry* / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry* / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D013267:Stilbenes; D011794:Quercetin; D019363:Cytochrome P-450 CYP1A1; D003474:Curcumin; D000077185:Resveratrol