Activities of a non-classical estrogen, Z-bis-dehydrodoisynolic acid, with ERalpha and ERbeta.
Activities of a non-classical estrogen, Z-bis-dehydrodoisynolic acid, with ERalpha and ERbeta.
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非经典雌激素 Z-双-脱氢异辛醇酸与 ERα 和 ERβ 的活性。
DOI：
10.1016/s0960-0760(02)00150-4
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Adler,Stuart
中科院分区：
文献类型：
--
作者：
Meyers,CalY;Hou,Yuqing;Winters,ToddA;Banz,WilliamJ;Adler,Stuart
(±)-Z-bis-Dehydrodoisynolic acid [(±)-Z-BDDA] is highly estrogenic in vivo, yet binds to estrogen receptor (ER) poorly. This paradox has raised the possibility of alternative ERs and/or molecular mechanisms. To address the possibility of high activities of Z-BDDA with ERβ, we determined the activities of (+)-Z-BDDA and (−)-Z-BDDA, in cell culture and in vitro, comparing ERβ to ERα. Transfectional analysis in Hela cells showed (−)-Z-BDDA is an agonist for gene activation with both ERα (EC50≅0.3nM) and ERβ (EC50≅5nM), while little to no activity was observed with (+)-Z-BDDA. Similarly, in gene repression assays, (−)-Z-BDDA was active (EC50≅0.2nM), but again minimal activity was exhibited by (+)-Z-BDDA. Binding to ERα and ERβ in vitro used both competition and a direct binding assay. For ERα, the relative affinity of (−)-Z-BDDA was approximately 6% by competition and 1.7% by direct binding versus 17β-estradiol (E2; 100%), while (+)-Z-BDDA also demonstrated binding, but with relative affinities of only 0.08% by competition and 0.3% by the direct assay. For ERβ, the affinity of (−)-Z-BDDA was approximately 7% by competition and 1.5% by the direct assay relative to E2 (100%), while (+)-Z-BDDA had lower affinity, approximately 0.2% that of E2 by both assays. The paradox of potent in vivo activity but lower activity in receptor binding and in cell culture reporter gene assays, previously seen with ERα is now also associated with ERβ. The failure of ERβ to explain the activity–binding paradox indicates the need for additional in vivo metabolic and pharmacokinetic studies and continued consideration of alternative mechanisms.
