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洋地黄与大鼠子宫中雌二醇结合位点的相互作用机制。

Mechanism of interaction of digitalis with estradiol binding sites in rat uteri.

作者信息

Rifka S M, Pita J C, Loriaux D L

出版信息

Endocrinology. 1976 Oct;99(4):1091-6. doi: 10.1210/endo-99-4-1091.

Abstract

Digitalis preparations have a weak estrogenic effect in man. The data in animals are equivocal. We have studied.the biologic effect of both digitoxin and digoxin on the rat uterus in vivo and the interaction of these drugs with the rat uterus estrogen receptor in vitro. Digitoxin and estradiol significantly increased the uterine weight of immature rats, while digoxin did not. The interaction of digitoxin and digoxin with the rat uterus estrogen cytosol receptor was studied using protamine sulfate precipitation and dextran-coated charcoal (DCC) assays. Both methods gave a Kd for the estradiol-receptor interaction between 0.8-3.1 X 10(-9) M (n = 20). Digitoxin at concentrations of 0.5-2.0 X 10(-6) M significantly inhibited the binding of estradiol to the specific or saturable binding sites with minimal inhibition of hormonal binding to nonspecific sites. The binding was competitive with a calculated Ki for digitoxin of 5.2-7.8 X 10(-7) M (n = 18). Digoxin failed to inhibit estradiol binding to the receptor protein in vitro. We conclude that digitoxin probably acts directly as a weak estrogen and that this effect probably explains the estrogen-like side effects seen with digitoxin therapy in man.

摘要

洋地黄制剂对人体有微弱的雌激素样作用。动物实验的数据并不明确。我们研究了洋地黄毒苷和地高辛对大鼠子宫的体内生物学效应,以及这些药物在体外与大鼠子宫雌激素受体的相互作用。洋地黄毒苷和雌二醇显著增加了未成熟大鼠的子宫重量,而地高辛则没有。使用硫酸鱼精蛋白沉淀法和葡聚糖包被活性炭(DCC)分析法研究了洋地黄毒苷和地高辛与大鼠子宫雌激素胞浆受体的相互作用。两种方法得出的雌二醇-受体相互作用的解离常数(Kd)在0.8 - 3.1×10⁻⁹ M之间(n = 20)。浓度为0.5 - 2.0×10⁻⁶ M的洋地黄毒苷显著抑制雌二醇与特异性或可饱和结合位点的结合,对激素与非特异性位点结合的抑制作用最小。这种结合具有竞争性,计算得出洋地黄毒苷的抑制常数(Ki)为5.2 - 7.8×10⁻⁷ M(n = 18)。地高辛在体外未能抑制雌二醇与受体蛋白的结合。我们得出结论,洋地黄毒苷可能直接作为一种弱雌激素起作用,这种作用可能解释了洋地黄毒苷治疗人体时出现的类似雌激素的副作用。

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