title: Glucuronidation does not suppress the estrogenic activity of quercetin in yeast and human breast cancer cell model systems.
abstract: Several plant-derived molecules, referred to as phytoestrogens, are thought to mimic the actions of endogenous estrogens. Among these, quercetin, one of the most widespread flavonoids in the plant kingdom, has been reported as estrogenic in some occasions. However, quercetin occurs in substantial amounts as glycosides such as quercetin-3-O-glucoside (isoquercitrin) and quercetin-3-O-rutinoside (rutin) in dietary sources. It is now well established that quercetin undergoes substantial phase II metabolism after ingestion by humans, with plasma metabolites after a normal dietary intake rarely exceeding nmol/L concentrations. Therefore, attributing phytoestrogenic activity to flavonoids without taking into account the fact that it is their phase II metabolites that enter the circulatory system, will almost certainly lead to misleading conclusions. With the aim of clarifying the above issue, the goal of the present study was to determine if plant-associated quercetin glycosides and human phase II quercetin metabolites, actually found in human biological fluids after intake of quercetin containing foods, are capable of interacting with the estrogen receptors (ER). To this end, we used a yeast-based two-hybrid system and an estrogen response element-luciferase reporter assay in an ER-positive human cell line (MCF-7) to probe the ER interaction capacities of quercetin and its derivatives. Our results show that quercetin-3-O-glucuronide, one of the main human phase II metabolites produced after intake of dietary quercetin, displays ERα- and ERβ-dependent estrogenic activity, the functional consequences of which might be related to the protective activity of diets rich in quercetin glycosides.
authors.affiliation: Laboratory of Functional Genomics and Protein Engineering, Biochemistry and Molecular Biology Unit, Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ruotolo
authors.affiliation: The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, Medical School Building C, University of Parma, 43125 Parma, Italy; LS9 Bioactives and Health, Interlab Group, Department of Food Science, University of Parma, Parma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Calani
authors.affiliation: The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, Medical School Building C, University of Parma, 43125 Parma, Italy.
authors.forename: Furio
authors.initials: F
authors.lastname: Brighenti
authors.affiliation: Plant Products and Human Nutrition Group, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Crozier
authors.affiliation: Laboratory of Functional Genomics and Protein Engineering, Biochemistry and Molecular Biology Unit, Department of Life Sciences, University of Parma, 43124 Parma, Italy. Electronic address: s.ottonello@unipr.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Ottonello
authors.affiliation: The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food Science, Medical School Building C, University of Parma, 43125 Parma, Italy; LS9 Bioactives and Health, Interlab Group, Department of Food Science, University of Parma, Parma, Italy. Electronic address: daniele.delrio@unipr.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Del Rio
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D020719:Glucuronides / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D048789:Phytoestrogens / Q000737:chemistry* / Q000494:pharmacology*; D011794:Quercetin / Q000737:chemistry* / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects*
chemical_list: D020719:Glucuronides; D048789:Phytoestrogens; D011794:Quercetin
keywords: Flavonols; Phytoestrogen; Quercetin; Quercetin metabolites