Effects of steroidal and non-steroidal antiandrogens on the androgen binding properties of the rat ventral prostate androgen receptor.
Effects of steroidal and non-steroidal antiandrogens on the androgen binding properties of the rat ventral prostate androgen receptor.
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类固醇和非类固醇抗雄激素对大鼠腹侧前列腺雄激素受体雄激素结合特性的影响。
DOI：
10.1016/0167-4889(91)90031-r
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Muldoon,TG
中科院分区：
文献类型：
--
作者：
Steinsapir,J;Mora,G;Muldoon,TG
甾体（醋酸环丙孕酮）和非甾体（RU23908和羟氟他胺）抗雄激素能够阻断睾丸激素诱导的1天切除兰科大鼠前列腺核雄激素受体（AR）的增加，但在同一动物模型中，单独给药RU23908和羟氟他胺增加核AR （RU23908 bb0羟氟他胺）。单独使用抗雄激素或单独使用睾酮诱导的核AR增加在给药后1小时被环己亚胺阻断，提示雄激素或抗雄激素诱导重新合成AR。伴随着核AR积累，睾酮能够诱导胞浆和微粒体AR的消耗。在抗雄激素存在的情况下，睾酮诱导的微粒体AR的消耗被阻断，而细胞质AR则不被阻断。与RU23908或羟氟他胺相比，醋酸环丙孕酮对微粒体AR和细胞质AR具有更高的相对结合亲和力（RBA）。这种现象与这些化合物对微粒体AR的雄激素相关率的抑制程度很好地一致。RBA与激素与受体结合的初始速率的抑制之间的这种相关性在细胞质AR中没有发现。结果表明，抗雄激素不是雄激素作用的“纯”拮抗剂，在缺乏睾丸激素的情况下，它们是有效的激动剂。此外，睾酮单独或抗雄激素本身通过蛋白质合成依赖的作用机制，在大鼠腹侧前列腺中急剧调节AR水平。
Steroidal (cyproterone acetate) and non-steroidal (RU23908 and hydroxyflutamide) antiandrogens are able to block testosterone-induced increases in nuclear androgen receptor (AR) in the prostate of 1-day orchidectomized rats, but when given alone, RU23908 and hydroxyflutamide increase nuclear AR (RU23908 > hydroxyflutamide) in the same animal model. The increases in nuclear AR induced by antiandrogen alone or with testosterone alone are blocked by cycloheximide 1 h after administration, suggesting that androgen or antiandrogens induce de novo AR synthesis. Concomitant to nuclear AR accumulation, testosterone is able to induce depletion of cytosol and microsomal AR. Blockade of testosterone-induced depletion of microsomal AR, but not of cytosol AR, occurs in the presence of antiandrogens. Cyproterone acetate has a higher relative binding affinity (RBA) for microsomal AR and cytosol AR than RU23908 or hydroxyflutamide. This phenomenon is in good agreement with the degree of inhibition by these compounds of the association rate of androgen for the microsomal AR. This correlation between RBA and inhibition of the initial rate of hormone binding to the receptor is not found for cytosol AR. The results show that antiandrogens are not ‘pure’ antagonists of androgen action and they are potent agonists in the absence of testosterone. Furthermore, testosterone alone or antiandrogens per se regulate AR levels acutely by protein-synthesis dependent mechanisms of action, in rat ventral prostate.