de Gooyer Marcel E, Deckers Godefrides H, Schoonen Willem G E J, Verheul Herman A M, Kloosterboer Helenius J
Department of Pharmacology, Research and Development, NV Organon, Molenstraat 110, P.O. Box 20, 5340 BH Oss, The Netherlands.
Steroids. 2003 Jan;68(1):21-30. doi: 10.1016/s0039-128x(02)00112-5.
The receptor profiles and in vivo activity of tibolone, and its primary metabolites, Delta(4)-isomer, and 3alpha- and 3beta-hydroxytibolone, were studied and compared to those of structurally related compounds. The Delta(4)-isomer was the strongest binder and activator of the progesterone receptor (PR); tibolone was 10 times weaker in binding and half as potent in transactivation of PR; 3alpha- and 3beta-hydroxytibolone did not bind or activate PR. In rabbits oral tibolone produced a minor progestagenic effect in the endometrium, whereas co-administration of tibolone and the anti-estrogen ICI 164,384 unmasked tibolone's progestagenic effect. 3-Hydroxytibolones were the strongest binders and activators of the estrogen receptors (ERs), with greater affinity for ERalpha than for ERbeta. Tibolone showed weaker binding and activation of both ERs and the Delta(4)-isomer has a binding and activation activity of less than 0.1% of E2 for ERalpha or ERbeta. Tamoxifen and 4-hydroxytamoxifen showed partial ERalpha agonistic effects with a maximal response of 12% and raloxifene of 3-5%. Oral administration of 1mg tibolone to ovariectomized rats induced an estrogenic effect on vaginal epithelium. The Delta(4)-isomer was a stronger binder and activator of the androgen receptor (AR) than tibolone; both 3-hydroxytibolones did not bind or activate AR. Introducing a 7alpha-methyl group decreased progestagenic and increased androgenic activity. We conclude that the progestagenic and androgenic activities of tibolone are mediated by the Delta(4)-isomer, and the estrogenic activity, by the 3-hydroxytibolones. The estrogenic activity of the 3-hydroxytibolones masked the progestagenic activity of tibolone in rabbit endometrium. Full estrogenic response was observed in rat vaginal tissue after oral administration of tibolone.
研究了替勃龙及其主要代谢产物Δ⁴-异构体、3α-羟基替勃龙和3β-羟基替勃龙的受体谱及体内活性，并与结构相关化合物进行了比较。Δ⁴-异构体是最强的孕激素受体（PR）结合剂和激活剂；替勃龙的结合能力弱10倍，PR反式激活能力仅为其一半；3α-羟基替勃龙和3β-羟基替勃龙不结合或激活PR。在兔体内，口服替勃龙对子宫内膜产生轻微的孕激素样作用，而替勃龙与抗雌激素ICI 164,384共同给药则可揭示替勃龙的孕激素样作用。3-羟基替勃龙是雌激素受体（ERs）最强的结合剂和激活剂，对ERα的亲和力大于对ERβ的亲和力。替勃龙对两种ERs的结合和激活作用较弱，Δ⁴-异构体对ERα或ERβ的结合和激活活性不到E2的0.1%。他莫昔芬和4-羟基他莫昔芬表现出部分ERα激动作用，最大反应率为12%，雷洛昔芬为3 - 5%。给去卵巢大鼠口服1mg替勃龙可对阴道上皮产生雌激素样作用。Δ⁴-异构体是比替勃龙更强的雄激素受体（AR）结合剂和激活剂；两种3-羟基替勃龙均不结合或激活AR。引入7α-甲基可降低孕激素活性并增加雄激素活性。我们得出结论，替勃龙的孕激素和雄激素活性由Δ⁴-异构体介导，而雌激素活性由3-羟基替勃龙介导。3-羟基替勃龙的雌激素活性掩盖了替勃龙在兔子宫内膜中的孕激素活性。口服替勃龙后，在大鼠阴道组织中观察到了完全的雌激素反应。
