Diarylheptanoid phytoestrogens isolated from the medicinal plant Curcuma comosa: biologic actions in vitro and in vivo indicate estrogen receptor-dependent mechanisms.
Diarylheptanoid phytoestrogens isolated from the medicinal plant Curcuma comosa: biologic actions in vitro and in vivo indicate estrogen receptor-dependent mechanisms.
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DOI：
10.1289/ehp.0900613
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发表时间：
2009-07
影响因子：
10.4
通讯作者：
Korach KS
中科院分区：
文献类型：
--
作者：
Winuthayanon W;Piyachaturawat P;Suksamrarn A;Ponglikitmongkol M;Arao Y;Hewitt SC;Korach KS
姜黄中的二芳基庚烷类化合物最近被确认为植物雌激素。然而，他们的行动背后的机制尚未确定。我们在体外和体内表征了三个天然存在的活性二芳基庚烷类化合物的雌激素活性。我们用实时定量聚合酶链式反应、哺乳动物细胞转染模型和子宫滋养细胞实验研究了二芳基庚烷类化合物(3S)-1，7-二苯基-(6E)-6-庚烯-3-醇(D1)、1，7-二苯基-(6E)-6-庚烯-3-酮(D2)和(3R)-1，7-二苯基-(4E，6E)-4，6-庚二烯-3-醇(D3)的雌激素作用机制。所有二芳基庚烷类化合物都上调雌激素反应性乳腺癌细胞(MCF-7)中的雌激素反应性基因。在转染了雌激素受体(ER)β或不同ERα受体功能突变体和Vit-ere-Tata-Luc报告基因的HepG2细胞中，所有二芳基庚烷类化合物都通过配体依赖的人ERα-ERE途径诱导转录，该途径可被ER拮抗剂ICI182,780所阻断，而只有D2能被ERβ激活。缺乏AF2(激活功能2)区的ERα突变体对17β-雌二醇(E2)或任何二芳基庚烷类化合物都不反应，而缺乏AF1结构域的ERα表现出类似野生型的活性。D3能显著增加去卵巢小鼠的子宫重量和子宫上皮细胞的增殖，而D1和D2无明显作用。D3和E2一样，上调乳铁蛋白(LTF)基因表达。ICI182,780抑制子宫对D3的反应。此外，D3刺激经典的(AQP5)和非经典的(CDKN1A)ER介导的基因调控。结果表明，D3二芳基庚烷类化合物在体外和体内都是ER的激动剂，其生物学作用是ERα选择性的，特别需要AF2功能，涉及ER的直接结合和ERE不依赖的基因调控。
Diarylheptanoids isolated from Curcuma comosa Roxb. have been recently identified as phyto estrogens. However, the mechanism underlying their actions has not yet been identified. We characterized the estrogenic activity of three active naturally occurring diarylheptanoids both in vitro and in vivo. We characterized mechanisms of estrogenic action of the diarylheptanoids (3S)-1,7-diphenyl-(6E)-6-hepten-3-ol (D1), 1,7-diphenyl-(6E)-6-hepten-3-one (D2), and (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (D3) by using a real-time polymerase chain reaction assay, a mammalian transfection model, and a uterotrophic assay in mice. All diarylheptanoids up-regulated estrogen-responsive genes in estrogen-responsive breast cancer cells (MCF-7). In HepG2 cells transfected with estrogen receptor (ER) β or different ERα functional receptor mutants and the Vit-ERE-TATA-Luc reporter gene, all diarylheptanoids induced transcription through a ligand-dependent human ERα-ERE–driven pathway, which was abolished with ICI 182,780 (ER antagonist), whereas only D2 was active with ERβ. An ERα mutant lacking the functional AF2 (activation function 2) region was not responsive to 17β-estradiol (E2) or to any of the diarylheptanoids, whereas ERα lacking the AF1 domain exhibited wild-type–like activity. D3 markedly increased uterine weight and proliferation of the uterine epithelium in ovariectomized mice, whereas D1 and D2 were inactive. D3, like E2, up-regulated lactoferrin (Ltf) gene expression. The responses to D3 in the uterus were inhibited by ICI 182,780. In addition, D3 stimulated both classical (Aqp5) and nonclassical (Cdkn1a) ER-mediated gene regulation. The results suggest that the D3 diarylheptanoid is an agonist for ER both in vitro and in vivo, and its biological action is ERα selective, specifically requiring AF2 function, and involves direct binding via ER as well as ERE-independent gene regulation.
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影响因子：
4.8
作者：
Kuiper, GGJM;Lemmen, JG;Gustafsson, JÄ
通讯作者：
Gustafsson, JÄ
影响因子：
--
作者：
Hewitt, SC;Collins, J;Korach, KS
通讯作者：
Korach, KS
影响因子：
--
作者：
Hewitt, SC;Deroo, BJ;Korach, KS
通讯作者：
Korach, KS
影响因子：
2.1
作者：
Kobayashi, Mika;Takahashi, Eri;Iguchi, Taisen
通讯作者：
Iguchi, Taisen
影响因子：
10.4
作者：
Jorgensen, M;Vendelbo, B;Leffers, H
通讯作者：
Leffers, H