Albertson B D, Hill R B, Sprague K A, Wood K E, Nieman L K, Loriaux D L
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Eur J Endocrinol. 1994 Feb;130(2):195-200. doi: 10.1530/eje.0.1300195.
RU486, a synthetic steroid receptor antagonist, has strong antiprogesterone and antiglucocorticoid properties. Chronic RU486 administration in two patients with ectopic secretion of adrenocorticotropin (ACTH) has been associated with decreasing plasma cortisol concentrations. One explanation of this finding is that RU486 may directly inhibit adrenal steroidogenesis. To test this hypothesis, we measured the effect of RU486 on specific steroidogenic enzymatic steps using an in vivo rat and an in vitro monkey model. Hypophysectomized-castrated-ACTH-replaced Sprague-Dawley rats were given RU486 i.p. at daily doses of 0, 0.0005, 0.005, 0.05, 0.5 and 5 mg/kg body weight per day for 7 days. The animals were sacrificed, and blood and adrenal glands collected. Adrenal cortical mitochondria and microsomes were purified from the rats and from two untreated Cynomolgus macaque monkeys. Specific steroidogenic enzyme activities were measured in the rat by the incorporation of 14C-labeled steroid substrates into products. A similar protocol was used to assay the steroidogenesis in the monkey adrenal fractions in the presence and absence of added RU486. Although rat adrenal weights decreased significantly at the highest RU486 dose, plasma levels of corticosterone were similar in control and treated rats. Rat adrenal 3 beta-hydroxysteroid dehydrogenase/isomerase (3-HSD), 21-hydroxylase (21-OH) and 11-hydroxylase (11-OH) activities decreased with increasing RU486 doses, with 21-OH and 11-OH being most severely affected. Monkey adrenal 3-HSD, 21-OH, 11-OH, 17-hydroxylase and 17,20-desmolase similarly decreased in the presence of increasing in vitro concentrations of RU486.(ABSTRACT TRUNCATED AT 250 WORDS)
米非司酮是一种合成类固醇受体拮抗剂，具有强大的抗孕激素和抗糖皮质激素特性。在两名促肾上腺皮质激素（ACTH）异位分泌患者中，长期服用米非司酮与血浆皮质醇浓度降低有关。这一发现的一种解释是，米非司酮可能直接抑制肾上腺类固醇生成。为验证这一假设，我们使用体内大鼠模型和体外猴模型，测量了米非司酮对特定类固醇生成酶步骤的影响。对垂体切除、去势并补充ACTH的斯普拉格-道利大鼠，每天腹腔注射米非司酮，剂量分别为0、0.0005、0.005、0.05、0.5和5mg/kg体重，持续7天。处死动物后，采集血液和肾上腺。从大鼠以及两只未经处理的食蟹猕猴中纯化肾上腺皮质线粒体和微粒体。通过将14C标记的类固醇底物掺入产物中，测定大鼠体内特定类固醇生成酶的活性。在添加和不添加米非司酮的情况下，采用类似方案检测猴肾上腺组分中的类固醇生成。尽管在最高米非司酮剂量下大鼠肾上腺重量显著降低，但对照大鼠和处理大鼠的血浆皮质酮水平相似。随着米非司酮剂量增加，大鼠肾上腺3β-羟基类固醇脱氢酶/异构酶（3-HSD）、21-羟化酶（21-OH）和11-羟化酶（11-OH）活性降低，其中21-OH和11-OH受影响最严重。在体外米非司酮浓度增加时，猴肾上腺3-HSD、21-OH、11-OH、17-羟化酶和17,20-裂解酶活性同样降低。（摘要截选至250词）
