用实验系统研究雄激素的合成代谢作用。

G Michel, E E Baulieu
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引用次数: 0

摘要

由于男性的骨骼肌比女性更发达,人们认为雄激素可能与肌肉萎缩或合成代谢作用有关。在这方面,许多研究试图回答这个问题:雄激素(或它们的一些代谢物)是否负责肌萎缩作用,以及通过什么机制?它们是像作用于其他靶器官一样直接作用于骨骼肌,还是间接作用于肌肉,可能是通过次级兴奋剂(例如在肝脏中合成)?现在有证据表明,在大鼠的骨骼肌中,雄激素可能通过与细胞可溶性受体的结合而起作用,就像它们在腹侧前列腺中所做的那样。这种受体与所有其他雄激素受体具有类似的特性。它是一种蛋白质(酶敏感)“8S”成分结合睾酮和雄甾酮,亲和力高,容量小;它不结合雄甾二醇。这一发现以及在睾酮作用后肌细胞培养中3h -胸腺嘧啶在细胞核中掺入的增加和蛋白质合成的增加支持了肌肉细胞是骨骼肌中雄激素的直接靶点的概念。目前,用粗细胞质制剂还不能定量评估受体结合的类固醇特异性。虽然在前列腺腹侧,雄甾酮具有更高的亲和力,但结合实验尚未表明,在肌肉中,睾酮的高亲和力是否与两种类固醇的不同结合有关,或者与提取物中存在的酶的复杂作用有关。事实上,在与结合测定相同的实验条件下,获得了5α -还原酶和3α, β -羟基类固醇还原酶活性的证据。因此,通过转化为不与受体结合的雄甾二醇,或转化为雄甾酮而增加表观睾酮结合,可以降低肌肉中睾酮的表观结合。因此,睾酮、雄甾酮或其他天然类固醇是否是大鼠骨骼肌中最有效的肌促激素的问题仍然没有解决。然而,这种动物模型允许研究雄激素对肌肉作用的某些有趣方面。当受体制剂部分纯化且不受代谢酶污染时,可以测试不同的天然或合成类固醇在肌肉中的亲和力和合成代谢有效性。如果受体的多样性使区分肌萎缩作用和阳痿活动成为可能,这将是药理学上的兴趣。这种体外系统允许研究分子的作用机制,这些分子在体内可能具有抗雄激素作用,值得注意的是,放射性睾酮和雄甾酮可以通过过量的雌二醇、孕酮和醋酸环丙孕酮来竞争受体结合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
An approach to the anabolic action of androgens by an experimental system.

As skeletal muscle is more developed in the male than in the female, it is supposed that androgens might be responsible for myotrophic or anabolic action. In this respect, many studies were made to try to answer the question: are androgens (or some of their metabolites) responsible for myotrophic action and by what mechanism? Do they act directly on skeletal muscle as on other target organs, or have they an indirect action on muscle, perhaps through a secondary stimulant (for instance synthesized in the liver)? Evidence is now presented that, in the rat's skeletal muscle, androgens likely act through the binding to a cytosoluble receptor, as they do in the ventral prostate. This receptor has analogous properties to all other androgen receptors. It is a proteinaceous (pronase sensible) "8S" component binding testosterone and androstanolone with high affinity and small capacity; it does not bind androstanediols. This finding and the increased incorporation of 3H-thymidine in nuclei and increased protein synthesis obtained in muscle cell culture after action of testosterone favour the concept that muscular cells are direct targets of androgens in skeletal muscles. Presently, the steroid specificity of receptor binding cannot be assessed quantitatively with crude cytosol preparation. While in ventral prostate, androstanolone has a higher affinity, the binding experiments have not yet indicated in muscle if the higher affinity of testosterone is related to differential binding of the two steroids, or to the complex effects of enzymes present in the extracts. In fact, evidence was obtained for 5alpha-reductase and 3alpha,beta-hydroxysteroid reductase activities under the same experimental conditions as for binding determinations. Therefore, the apparent antrostanolone binding in muscle could be lowered by transformation into androstanediols not binding to receptor, or the increase of apparent testosterone binding due to transformation into androstanolone. So the problem of whether testosterone or androstanolone or another natural steroid is the most effective myotrophic hormone in rat skeletal muscle remains unsolved. However, this animal model allows the study of certain interesting aspects of action of androgens on muscle. When receptor preparations are partially purified and not contaminated by metabolizing enzymes, different natural or synthetic steroids can be tested as to their affinity and anabolic effectiveness in muscle. It would be of pharmacological interest if receptor diversity made it possible to distinguish myotrophic action from virilizing activities. This in vitro system allows studying the mechanism of action of molecules which could have in vivo an anti-androgen effect and it is remarkable that radioactive testosterone and androstanolone can compete for receptor binding by an excess of estradiol, progesterone and cyproterone acetate...

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