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.
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.
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Quercetin-3-O-glucronide 抑制去甲肾上腺素与 α2-肾上腺素能受体的结合，从而抑制 MCF-10A 细胞中 4-羟基雌二醇和去甲肾上腺素处理引起的 DNA 损伤。
DOI：
10.1016/j.jsbmb.2014.02.014
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Shimoi K.
中科院分区：
文献类型：
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作者：
Yamazki S.;Sakakibara H.;Takemura H.;Yasuda M.;Shimoi K.
乳腺癌的风险因素包括雌激素，如17β-雌二醇(17-雌二醇，E2)和高压力水平。4-羟基雌二醇(4-OHE2)是由细胞色素P450 1b1优先生成的E2的代谢产物，它被氧化成E2-3，4-苯二酚，再与DNA反应生成具有遗传毒性和致癌性的脱色加合物。内源性儿茶酚胺，如肾上腺素(A)和去甲肾上腺素(NA)，在应激时从肾上腺和交感神经系统释放出来。在这里，我们发现，4-羟雌二醇(3-μM)和去甲肾上腺素(NA，3-NM)处理显著地诱导组蛋白H_2AX(γ-H_2AX)和脱嘌呤(AP)位点的磷酸化，组蛋白H_2AX是最早的DNA损伤指标之一，它通过α2-肾上腺素能受体(α2-AR)在人乳腺上皮细胞上发生磷酸化。由于先前的流行病学研究表明，较高的黄酮类化合物摄入量与乳腺癌风险之间存在负相关，因此我们研究了血液中的一种循环代谢产物--槲皮素-3-O-葡萄糖醛酸苷(Q3G)对4-OHE_2和NA诱导的γ-H_2AX和AP位点的影响。Q3G(0.1MμM)可抑制其诱导，并抑制[~3H]-NA与α_2-AR的结合。这些结果表明，Q3G作为一种α-2-AR拮抗剂，可以作为应激促进乳腺癌的化学预防药物。
Risk factors for breast cancer include estrogens such as 17β-estradiol (E2) and high stress levels. 4-Hydroxyestradiol (4-OHE2), a metabolite of E2formed 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) sitesviathe 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 [3H]-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.