Michel G, Baulieu E E
Environ Qual Saf Suppl. 1976(5):54-9.
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...
由于男性的骨骼肌比女性更发达，因此推测雄激素可能是导致肌营养或合成代谢作用的原因。在这方面，人们进行了许多研究，试图回答以下问题：雄激素（或其某些代谢产物）是否是导致肌营养作用的原因，其作用机制是什么？它们是像作用于其他靶器官一样直接作用于骨骼肌，还是可能通过 secondary stimulant（例如在肝脏中合成的物质）对肌肉产生间接作用？现在有证据表明，在大鼠骨骼肌中，雄激素可能像在腹侧前列腺中一样，通过与一种可溶性细胞溶质受体结合而发挥作用。这种受体具有与所有其他雄激素受体类似的特性。它是一种蛋白质类（对链霉蛋白酶敏感）的“8S”成分，能以高亲和力和低容量结合睾酮和雄甾烷醇；它不结合雄甾二醇。这一发现以及睾酮作用后肌肉细胞培养物中细胞核内3H-胸腺嘧啶掺入增加和蛋白质合成增加，都支持了肌肉细胞是骨骼肌中雄激素直接靶标的观点。目前，用粗制细胞溶质制剂无法定量评估受体结合的类固醇特异性。在腹侧前列腺中，雄甾烷醇具有更高的亲和力，但结合实验尚未表明在肌肉中，睾酮的更高亲和力是与这两种类固醇的差异结合有关，还是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，已获得了5α-还原酶和3α,β-羟基类固醇还原酶活性的证据。因此，肌肉中明显的雄甾烷醇结合可能会因转化为不与受体结合的雄甾二醇而降低，或者因转化为雄甾烷醇而导致明显的睾酮结合增加。所以，睾酮、雄甾烷醇或另一种天然类固醇是否是大鼠骨骼肌中最有效的肌营养激素的问题仍然没有解决。然而，这个动物模型有助于研究雄激素对肌肉作用的某些有趣方面。当受体制剂被部分纯化且未被代谢酶污染时，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效力。如果受体多样性能够区分肌营养作用和男性化活性，那将具有药理学意义。这个体外系统有助于研究在体内可能具有抗雄激素作用的分子的作用机制，值得注意的是，放射性睾酮和雄甾烷醇会被过量的雌二醇、孕酮和醋酸环丙孕酮竞争受体结合……
