title: Quercetin-3-O-glucronide inhibits noradrenaline binding to α2-adrenergic receptor, thus suppressing DNA damage induced by treatment with 4-hydroxyestradiol and noradrenaline in MCF-10A cells.
abstract: Risk factors for breast cancer include estrogens such as 17β-estradiol (E2) and high stress levels. 4-Hydroxyestradiol (4-OHE2), a metabolite of E2 formed preferentially by cytochrome P450 1B1, is oxidized to E2-3,4-quinone, which reacts with DNA to form depurinating adducts that exert genotoxicity and carcinogenicity. Endogenous catecholamines such as adrenaline (A) and noradrenaline (NA) are released from the adrenal gland and sympathetic nervous system during exposure to stress. Here, we found that treatment with 4-OHE2 (3 μM) and NA (3 nM) significantly induced the phosphorylation of histone H2AX (γ-H2AX), one of the earliest indicators of DNA damage, and apurinic (AP) sites via the α2-adrenergic receptor (α2-AR) in human mammary epithelial MCF-10A cells. As an inverse association between a higher intake of flavonoids and breast cancer risk has previously been suggested from epidemiological studies, we investigated the effects of quercetin-3-O-glucuronide (Q3G), a circulating metabolite of quercetin in the blood, on 4-OHE2- and NA-induced γ-H2AX and AP sites. Q3G (0.1 μM) suppressed their induction and inhibited the binding of [(3)H]-NA to α2-AR. These results suggest that Q3G acts as an α2-AR antagonist and that it could be used as a chemopreventive agent for stress-promoted breast cancer.
authors.affiliation: Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-kibanadai-nishi, Miyazaki 889-2192, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakakibara
authors.affiliation: Faculty of Home Economics, Aichi Gakusen University, 28 Hegoshi-cho Kawakaminari, Okazaki 444-8520, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Takemura
authors.affiliation: Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: shimoi@u-shizuoka-ken.ac.jp.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Shimoi
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D002393:Estrogens, Catechol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009638:Norepinephrine / Q000494:pharmacology*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000316:Adrenergic alpha-Agonists; D002393:Estrogens, Catechol; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; C443401:quercetin 3-O-glucuronide; D011794:Quercetin; C014036:4-hydroxyestradiol; D009638:Norepinephrine
keywords: 4-Hydroxyestradiol; DNA damage; Human mammary epithelial MCF-10A cells; Noradrenaline; Quercetin-3-O-glucronide; α(2)-Adrenergic receptor