Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β
Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β
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DOI：
10.1210/en.139.10.4252
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发表时间：
1998-10-01
期刊：
影响因子：
4.8
通讯作者：
Gustafsson, JÄ
中科院分区：
文献类型：
--
作者：
Kuiper, GGJM;Lemmen, JG;Gustafsson, JÄ
大鼠、小鼠和人的雌激素受体(ER)以ERα和ERβ两种亚型存在，它们在C端的配体结合域和N端的反式激活域中存在差异。在这项研究中，我们研究了环境化学物质和植物雌激素与ERα或ERβ蛋白的竞争结合实验中的雌激素样活性，以及在瞬时基因表达实验中，通过在雌激素依赖的报告质粒存在下与重组人ERα或ERβ互补DNA(CDNA)共转染产生急性雌激素反应的细胞中的雌激素样反应。所有环境雌激素化学物质[多氯羟基联苯、二氯二苯基三氯乙烷(DDT)及其衍生物、烷基酚、双酚A、甲氧基氯和十氯酮]都与E-2以相似的偏好和程度竞争结合这两个ER亚型。在大多数情况下，相对结合亲和力(RBA)至少比E-2低1000倍。一些植物雌激素如香豆素、染料木素、芹菜素、柚皮素和山奈酚等与E-2竞争结合ERP的能力强于与ERα的结合。在100-1000 nM的浓度范围内，类雌激素化合物如壬基酚、双酚A，o，p‘-DDT和2’，4‘，6’-三氯-4-联苯酚可刺激ERα和ERβ的转录活性。植物雌激素，包括染料木素、香豆素和玉米赤霉烯酮，在1-10 nM的浓度下刺激这两种ER亚型的转录活性。在转录激活实验中，两个ER亚型的植物雌激素的雌激素样活性排名是不同的；即，对于ERα和E-2，E-2远大于玉米赤霉烯酮=Coumestrol>；genistein>；daidzein>；芹菜素=phloretin>；bichanin A=kaempferol=naringenin>；formononetin=iprafinone=quercetin=chrysin对于ERα和E-2远大于genistein=Coumestrol>；zearalenone>；Biochanin A=apigin=kaenerin=narempferenin>；phloretin=quercetin=prerceoneone=chrysin for ER。除玉米赤霉烯酮是ERα的完全激动剂和ERβ的混合激动剂-拮抗剂外，没有检测到植物雌激素的抗雌激素活性。综上所述，虽然工业来源的雌激素类化学物质的雌激素活性非常有限，但植物雌激素的雌激素活性是显著的，特别是对ERβ，它们可能触发许多由生理性雌激素引起的生物反应。
The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid.Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [H-3]-17 beta-estradiol (E-2) with high affinity [dissociation constant (K-d) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E-2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E-2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E-2 for binding to ERP than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E-2 much greater than zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E-2 much greater than genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.