Direct agonist/antagonist functions of dehydroepiandrosterone
Direct agonist/antagonist functions of dehydroepiandrosterone
复制标题
DOI：
10.1210/en.2005-0368
复制
发表时间：
2005-11-01
期刊：
影响因子：
4.8
通讯作者：
Reszka, AA
中科院分区：
文献类型：
--
作者：
Chen, F;Knecht, K;Reszka, AA
脱氢表雄酮（DHEA）在足月胎儿和30岁左右成人肾上腺分泌高峰。然后水平逐渐下降，这与外周组织中睾酮、双氢睾酮和雌激素水平下降有关。绝经后妇女补充DHEA可增加骨形成和骨密度，这种作用主要归因于外周向性激素的转化。在这项研究中，我们测试了DHEA对雄激素（AR）和雌激素（ER）受体的直接影响。DHEA与AR结合的Ki为1 μ M，这与小鼠乳腺肿瘤病毒和前列腺特异性抗原启动子上的AR转录拮抗作用有关，与比卡鲁胺的作用非常相似。与比卡鲁胺不同，DHEA刺激，而不是抑制，LNCaP细胞的生长，这表明可能与其他激素受体的相互作用。事实上，DHEA结合ER α和ER β，Ki值分别为1.1和0.5 μ M。尽管具有相似的结合亲和力，DHEA显示出ER β的优先激动作用，EC 50约为200 nM，在1 μ M时最大活化。对于ER α，我们发现在5 μ M时有30 - 70%的激动作用，这取决于测定。DHEA的生理水平约为30 nM，在前列腺中高达90 nM。30 nM的DHEA实际上足以激活ER β转录到与其循环浓度的雌激素相同的程度，并且当两者结合时可以看到累加效应。综上所述，DHEA具有生理相关的ER β直接激活的潜力。在足月和30岁时达到峰值水平，对AR和ER α的部分激动也有拮抗作用的可能。
Dehydroepiandrosterone ( DHEA) exhibits peak adrenal secretion in the fetus at term and around age 30 yr in the adult. Levels then progressively decline, which is associated with decreased levels of testosterone, dihydrotestosterone, and estrogen in peripheral tissues. DHEA supplementation in postmenopausal women increases bone formation and density, an effect mainly attributed to peripheral conversion to sex hormones. In this study, we tested DHEA for direct effects on the androgen (AR) and estrogen (ER) receptors. DHEA bound to AR with a Ki of 1 mu M, which was associated with AR transcriptional antagonism on both the mouse mammary tumor virus and prostate-specific antigen promoters, much like the effects of bicalutamide. Unlike bicalutamide, DHEA stimulated, rather than inhibited, LNCaP cell growth, suggesting possible interaction with other hormone receptors. Indeed DHEA bound to ER alpha and ER beta, with Ki values of 1.1 and 0.5 mu M, respectively. Despite the similar binding affinities, DHEA showed preferential agonism of ER beta with an EC50 of approximately 200 nM and maximal activation at 1 mu M. With ER alpha we found 30 - 70% agonism at 5 mu M, depending on the assay. Physiological levels of DHEA are approximately 30 nM and up to 90 nM in the prostate. DHEA at 30 nM is actually sufficient to activate ER beta transcription to the same degree as estrogen at its circulating concentration, and additive effects are seen when the two were combined. Taken together, DHEA has the potential for physiologically relevant direct activation of ER beta. With peak levels at term and age 30 yr, there is also a potential for antagonist effects on AR and partial agonism of ER alpha.