Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism.
Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism.
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植物雌激素和合成组合文库对芳香酶、雌激素生物合成和代谢的影响。
DOI：
10.1111/j.1749-6632.2001.tb03986.x
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发表时间：
2001
影响因子：
5.2
通讯作者：
Whetstone,JL
中科院分区：
文献类型：
--
作者：
Brueggemeier,RW;Gu,X;Mobley,JA;Joomprabutra,S;Bhat,AS;Whetstone,JL
翻译后摘要：大约60%的乳腺癌患者有激素依赖性乳腺癌含有雌激素受体，并需要雌激素的肿瘤生长。乳腺癌组织微环境中雌激素生物合成和代谢的程度影响乳腺肿瘤的发育和生长，内源性和外源性药物可能会改变乳腺活性雌激素及其代谢产物的水平。异黄酮类植物雌激素如染料木黄酮表现出许多生物化学活性，然而，它们对乳腺癌细胞中雌激素生物合成和代谢的影响尚未得到充分研究。用染料木黄酮（100 nM）处理MCF-7细胞（激素依赖性）和MBA-MB-231细胞（激素非依赖性）5天，然后用放射性标记的雌二醇（100 nM，2.5 μCi）孵育0至48 h。用乙酸乙酯提取培养基，并通过反相HPLC和放射性流动检测器分析有机残留物。在所有情况下形成的主要代谢产物是雌酮，尽管在细胞系和各种药物治疗之间观察到差异。与未处理的MDA-MB-231细胞（24 h时约为放射性的32.0%）相比，未处理的MCF-7细胞（24 h时约为放射性的9.3%）中雌酮的形成相对有限。用100 nM染料木黄酮处理MCF-7细胞，24 h内雌二醇转化为雌酮的转化率增加至19.5%。染料木黄酮对MDA-MB-231细胞中雌酮形成的影响导致37.7%的放射性为雌酮。因此，染料木黄酮治疗乳腺癌细胞导致17-β羟基类固醇脱氢酶活性增加和雌酮形成增加。通过蛋白质印迹证实氧化17-β羟基类固醇脱氢酶活性（II型）水平升高。因此，乳腺癌细胞暴露于染料木黄酮导致雌二醇转化为雌激素较弱或无活性的代谢物。正在研究外源性试剂（如药物和环境试剂）对乳腺组织芳香化酶的调节。苯并吡喃酮-环系统是一个相当感兴趣的分子支架，这种支架在具有弱芳香酶抑制活性的类黄酮天然产物中发现。药物化学的努力集中在多样化的苯并吡喃酮支架和利用组合化学方法来构建小的苯并吡喃酮库作为潜在的芳香酶抑制剂。在筛选试验中，初始文库中的几种化合物已显示出中等的芳香酶抑制活性。
Abstract:Approximately 60% of breast cancer patients have hormone‐dependent breast cancer containing estrogen receptors and requiring estrogen for tumor growth. The extent of estrogen biosynthesis and metabolism in the breast cancer tissue microenvironment influences breast‐tumor development and growth, and endogenous and exogenous agents may alter the levels of hormonally active estrogens and their metabolites. Isoflavonoid phytoestrogens such as genistein exhibit numerous biochemical activities; however, their effects on estrogen biosynthesis and metabolism in breast cancer cells have not been fully examined. MCF‐7 cells (hormone‐dependent) and MBA‐MB‐231 cells (hormone‐independent) were treated with genistein (100 nM) for five days and then incubated with radiolabeled estradiol (100 nM, 2.5 μCi) for 0 to 48 h. Media were extracted with ethyl acetate, and the organic residues analyzed by reverse‐phase HPLC with a radioactivity flow detector. The major metabolite formed in all cases is estrone, although differences were observed between the cell lines and the various drug treatments. The formation of estrone in untreated MCF‐7 cells (approximately 9.3% of radioactivity at 24 h) is relatively limited, in contrast to untreated MDA‐MB‐231 cells (approximately 32.0% of radioactivity at 24 h). Treatment of MCF‐7 cells with 100 nM genistein increased the conversion of estradiol to estrone up to 19.5% in 24 h. The effect of genistein on estrone formation in MDA‐MB‐231 cells resulted in 37.7% of the radioactivity being estrone. Thus, genistein treatment of breast cancer cells resulted in increased 17‐βhydroxysteroid dehydrogenase activity and elevated formation of estrone. Increased levels of oxidative 17‐βhydroxysteroid dehydrogenase activity (Type II) were confirmed by Western blots. Therefore, exposure of breast cancer cells to genistein results in elevated conversion of estradiol to estrogenically weaker or inactive metabolites. The regulation of breast‐tissue aromatase by exogenous agents such as drugs and environmental agents is being investigated. The benzopyranone‐ring system is a molecular scaffold of considerable interest, and this scaffold is found in flavonoid natural products that have weak aromatase inhibitory activity. Medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aromatase inhibitors. Several compounds in the initial libraries have demonstrated moderate aromatase inhibitory activity in screening assays.