Neubauer B L, Best K L, Blohm T R, Gates C, Goode R L, Hirsch K S, Laughlin M E, Petrow V, Smalstig E B, Stamm N B
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Prostate. 1993;23(3):181-99. doi: 10.1002/pros.2990230302.
LY207320 is an in vitro inhibitor (estimated IC50 = 0.06 microM) of steroid 5 alpha-reductase that catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT). In contrast, LY207320 was only moderately active against rat prostatic 5 alpha-reductase in vivo (32% inhibition at 50.0 mg/kg single dose). LY207320 did, however, inhibit the in vivo uptake of [3H]-T by the prostate. The antiprostatic and endocrine effects of this agent were evaluated following daily (21 days) administration to castrated, androgen-supplemented castrate, and intact rats. LY207320, which has modest progestational competitive binding activity, does not bind to rat prostatic androgen or uterine estrogen cytosolic receptors. In the castrated male rat, subcutaneously (s.c.) administered LY207320 had no androgen agonist activity, as evidenced by a lack of accessory sex organ weight gains. Administration of s.c. LY207320 to intact rats for 21 days at doses greater than 5.0 mg/kg-day produced significant (P < 0.05) reductions of seminal vesicle and ventral prostatic weights (maximal regression = -65% and -40% from control values, respectively at 50.0 mg/kg-day). The compound had no regressive activity on male accessory sex organs when administered orally. LY207320 did not alter circulating prolactin, LH, or corticosterone levels, but at high doses (> or = 50.0 mg/kg-day), lowered circulating T[-67% from intact control levels (P < 0.05)]. Histological analysis of the rat ventral prostates (RVPs) in LY207320-treated rats was consistent with an androgen-deprived state. Decreased circulating androgens and prostatic regression are associated with inhibition of testicular 17 alpha-hydroxy/C17,20-lyase enzyme activity (IC50 = 0.06 microM). These findings support the contention that LY207320 is a physiological antagonist of androgen action in male rats, and that its effects are mediated primarily through inhibition of testicular androgen production rather than accessory sex organ 5 alpha-reductase.
LY207320是一种类固醇5α-还原酶的体外抑制剂（估计IC50 = 0.06微摩尔），该酶催化睾酮（T）转化为二氢睾酮（DHT）。相比之下，LY207320在体内对大鼠前列腺5α-还原酶的活性仅为中等水平（单次剂量50.0毫克/千克时抑制率为32%）。然而，LY207320确实抑制了前列腺对[3H]-T的体内摄取。在对去势、雄激素补充的去势大鼠和完整大鼠每日（21天）给药后，评估了该药物的抗前列腺和内分泌作用。LY207320具有适度的孕激素竞争性结合活性，不与大鼠前列腺雄激素或子宫雌激素胞质受体结合。在去势雄性大鼠中，皮下注射LY207320没有雄激素激动剂活性，这表现为附属性器官重量没有增加。以大于5.0毫克/千克·天的剂量对完整大鼠皮下注射LY207320 21天，可使精囊和腹侧前列腺重量显著降低（P < 0.05）（最大消退率分别为对照值的-65%和-40%，在50.0毫克/千克·天时）。口服该化合物时，对雄性附属性器官没有消退活性。LY207320不会改变循环中的催乳素、促黄体生成素或皮质酮水平，但在高剂量（≥50.0毫克/千克·天）时会降低循环中的睾酮水平[比完整对照水平降低67%（P < 0.05）]。对LY207320处理的大鼠的大鼠腹侧前列腺（RVP）进行组织学分析，结果与雄激素剥夺状态一致。循环雄激素减少和前列腺消退与睾丸17α-羟基/C17,20-裂解酶活性受到抑制（IC50 = 那么，IC = 0.06微摩尔）有关。这些发现支持了LY207320是雄性大鼠雄激素作用的生理拮抗剂这一观点，并且其作用主要是通过抑制睾丸雄激素生成而非附属性器官5α-还原酶介导的。
