Prostatic involution in rats induced by a novel 5 alpha-reductase inhibitor, SK&F 105657: role for testosterone in the androgenic response.
Prostatic involution in rats induced by a novel 5 alpha-reductase inhibitor, SK&F 105657: role for testosterone in the androgenic response.
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新型 5α-还原酶抑制剂 SK 诱导大鼠前列腺退化
DOI：
10.1210/endo.130.2.1733716
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发表时间：
1992
期刊：
影响因子：
4.8
通讯作者：
J. Isaacs
中科院分区：
文献类型：
--
作者：
J. Lamb;H. English;Patricia L. Levandoski;G. Rhodes;Randall K. Johnson;J. Isaacs
在前列腺内，雄激素刺激腺细胞分泌和增殖，同时抑制腺细胞死亡。由于其占主导地位的核定位，对雄激素受体的亲和力更高，细胞内浓度比睾酮高10倍以上，双氢睾酮（DHT），而不是睾酮，似乎是完整男性宿主前列腺内的活性细胞内雄激素。然而，这个问题仍然没有答案，睾酮本身是否能够在前列腺中产生雄激素效应，而不被5 α-还原酶不可逆地转化为DHT。为了解决这个问题，一种新的死端（即产品）抑制剂的5 α-还原酶，SK&F 105657，给予完整的或阉割的雄性大鼠用外源性睾酮或DHT治疗。当以25 mg/kg的剂量每天口服两次时，SK&F 105657将用外源性睾酮维持的完整或去势大鼠的前列腺DHT含量降低到与手术去势产生的相同的低水平。然而，与去势不同，这种SK&F 105657治疗使前列腺睾酮含量增加超过5倍。前列腺DHT的减少与睾酮的升高相结合，这是由于5 α-还原酶活性的体内抑制所致，因为在用外源性DHT维持的去势大鼠中未观察到它们。用外源性睾酮和口服SK&F 105657（25 mg/kg，每日两次）治疗完整或去势的雄性大鼠导致前列腺分泌的实质性抑制、前列腺腺细胞增殖的抑制和前列腺细胞死亡的增加。然而，变化的幅度没有手术去势后观察到的那么大。然而，该结果对于5 α-还原酶抑制具有特异性，因为在给予外源性DHT的去势大鼠中未观察到这些结果。这些结果表明，如果前列腺睾酮含量升高到足够的水平，诱导雄激素效应，而不需要前列腺DHT含量升高。因此，睾酮转化为二氢睾酮似乎是放大前列腺雄激素刺激的一种手段。
Within the prostate, androgen stimulates glandular cell secretion and proliferation while inhibiting glandular cell death. Due to its predominant nuclear localization, higher affinity for the androgen receptor, and more than 10-fold higher intracellular concentration than testosterone, dihydrotestosterone (DHT), not testosterone, appears to be the active intracellular androgen within the prostate of intact male hosts. The issue has remained unanswered, however, whether testosterone itself, without irreversible conversion to DHT by the 5 alpha-reductase enzyme, is capable of androgenic effects in the prostate. To address this issue, a novel dead end (i.e. product) inhibitor of the 5 alpha-reductase enzyme, SK&F 105657, was administered to intact or castrated male rats treated with either exogeneous testosterone or DHT. When administered twice a day orally at 25 mg/kg.dose, SK&F 105657 reduced the prostatic DHT content of either intact or castrated rats maintained with exogeneous testosterone to the same low level as that produced by surgical castration. Unlike castration, however, such SK&F 105657 treatment increased the prostatic testosterone content by more than 5-fold. The decrease in prostatic DHT coupled with a raise in testosterone are specifically due to the in vivo inhibition of the 5 alpha-reductase activity, since they were not observed in castrated rats maintained with exogeneous DHT. Treatment of intact or castrated male rats with exogeneous testosterone and oral SK&F 105657 (25 mg/kg, twice daily) resulted in a substantial inhibition of prostatic secretion, an inhibition of prostatic glandular cell proliferation, and an increase in prostatic glandular cell death. The magnitude of the changes, however, was not as great as that observed after surgical castration. The results are, however, specific for 5 alpha-reductase inhibition, since they were not observed in castrated rats given exogeneous DHT. These results demonstrate that if the prostatic testosterone content is elevated to sufficient levels, androgenic effects are induced without a requirement for an elevation in prostatic DHT content. Thus, the conversion of testosterone to DHT appears to function as a means of amplifying androgenic stimulation in the prostate.
影响因子：
4.8
作者：
GRINO, PB;GRIFFIN, JE;WILSON, JD
通讯作者：
WILSON, JD
影响因子：
4.8
作者：
KYPRIANOU, N;ISAACS, JT
通讯作者：
ISAACS, JT