Bigsby R M, Young P C
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis 46202-5196.
Am J Obstet Gynecol. 1994 Jul;171(1):188-94. doi: 10.1016/0002-9378(94)90468-5.
Our purpose was to assess the estrogenic action of onapristone (ZK299).
Three rodent models of estrogen action in the uterus were used. Deoxyribonucleic acid synthesis in the uterine epithelium of neonatal mice was determined by thymidine autoradiography. In adult ovariectomized mice uterine wet weight and progesterone receptor and estrogen receptor concentrations were determined. In immature rats uterine deoxyribonucleic acid synthetic activity was determined by thymidine autoradiography, epithelial hypertrophy and stromal edema were assessed histomorphometrically, and complement C3 protein synthesis was assessed by metabolic labeling in vitro. The effects of ZK299 were challenged with the antiestrogens ICI164,384 and tamoxifen. The ability of ZK299 to displace tritiated estradiol from the estrogen receptor was assessed in cytosolic preparations from mouse uterus.
In the neonatal mouse ZK299 stimulated epithelial deoxyribonucleic acid synthesis; two other antiprogestins, RU486 and ZK98.734, had no effect. Three daily injections of ZK299 at 10 micrograms/gm body weight to 6-week-old ovariectomized mice increased uterine progesterone receptor 42%; this effect was blocked by ICI164,384. In another experiment three daily doses of ZK299 (20 micrograms/gm) to 10-week-old ovariectomized mice increased progesterone receptor concentration by 63% and uterine wet weight by 42%. In 21-day-old rats a single injection of ZK299 increased uterine epithelial deoxyribonucleic acid synthesis; this effect was blocked by tamoxifen. Both ZK299 and tamoxifen increased epithelial cell height and thymidine labeling in the stroma. ZK98.734 had no effect on epithelium or stroma. ZK299 also stimulated synthesis of complement C3 by uteri of immature rats. In competitive binding assays ZK299 exhibited weak relative binding affinity (0.05%) for mouse uterine estrogen receptor.
ZK299 can act as a weak estrogen in the rodent uterus, most likely through a direct, low-affinity interaction with the estrogen receptor. Because estrogens may increase the risk for endometrial, breast, and liver cancer, caution is warranted in long-term administration of this drug to women.
我们的目的是评估奥那司酮（ZK299）的雌激素作用。
使用了三种子宫中雌激素作用的啮齿动物模型。通过胸腺嘧啶核苷放射自显影术测定新生小鼠子宫上皮中的脱氧核糖核酸合成。在成年去卵巢小鼠中，测定子宫湿重、孕激素受体和雌激素受体浓度。在未成熟大鼠中，通过胸腺嘧啶核苷放射自显影术测定子宫脱氧核糖核酸合成活性，通过组织形态计量学评估上皮肥大和基质水肿，并通过体外代谢标记评估补体C3蛋白合成。用抗雌激素药物ICI164,384和他莫昔芬挑战ZK299的作用。在小鼠子宫的胞质制剂中评估ZK299从雌激素受体上置换氚标记雌二醇的能力。
在新生小鼠中，ZK299刺激上皮脱氧核糖核酸合成；另外两种抗孕激素RU486和ZK98.734没有作用。以10微克/克体重对6周龄去卵巢小鼠每日注射三次ZK299，可使子宫孕激素受体增加42%；这种作用被ICI164,384阻断。在另一项实验中，以20微克/克体重对10周龄去卵巢小鼠每日注射三次ZK299，可使孕激素受体浓度增加63%，子宫湿重增加42%。在21日龄大鼠中，单次注射ZK299可增加子宫上皮脱氧核糖核酸合成；这种作用被他莫昔芬阻断。ZK299和他莫昔芬均增加上皮细胞高度和基质中的胸腺嘧啶核苷标记。ZK98.734对上皮或基质没有作用。ZK299还刺激未成熟大鼠子宫补体C3的合成。在竞争性结合试验中，ZK299对小鼠子宫雌激素受体表现出较弱的相对结合亲和力（0.05%）。
ZK299在啮齿动物子宫中可作为一种弱雌激素起作用，很可能是通过与雌激素受体直接的低亲和力相互作用。由于雌激素可能增加子宫内膜癌、乳腺癌和肝癌的风险，因此在对女性长期使用该药时需谨慎。
