Bamberger C M, Chrousos G P
National Institutes of Health, National Institute of Child Health and Human Development, Developmental Endocrinology Branch, Bethesda, Maryland 20892, USA.
Ann N Y Acad Sci. 1995 Jun 12;761:296-310. doi: 10.1111/j.1749-6632.1995.tb31385.x.
RU 486 is a prototype glucocorticoid antagonist with strong antiglucocorticoid activity in vitro and in vivo. Studies of its molecular mechanism of action have provided invaluable insights in the complex activation cascade of the GR itself. RU 486 effectively antagonizes glucocorticoids in most glucocorticoid-sensitive systems. Agonist effects, however, have been observed in some in vitro and in vivo systems, but remain the exception. In humans, administration of RU 486 causes generalized glucocorticoid resistance with high levels of cortisol compensating for the peripheral receptor blockade. This state is similar to that of patients with generalized familial glucocorticoid resistance. Because of its HPA axis stimulatory effects, RU 486 has limited chronic utility as an antiglucocorticoid. To date, the application of RU 486 can only be recommended in inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other treatments. The unusually long half-life of this drug also poses problems with titrating its dose within a therapeutic range. The development of a short-acting, selective glucocorticoid antagonist is therefore, a desirable goal of future research.
RU 486是一种原型糖皮质激素拮抗剂，在体外和体内均具有强大的抗糖皮质激素活性。对其作用分子机制的研究为糖皮质激素受体（GR）自身复杂的激活级联反应提供了宝贵的见解。在大多数对糖皮质激素敏感的系统中，RU 486能有效拮抗糖皮质激素。然而，在一些体外和体内系统中也观察到了激动剂效应，但仍属例外情况。在人类中，给予RU 486会导致全身性糖皮质激素抵抗，高水平的皮质醇可补偿外周受体的阻滞。这种状态类似于全身性家族性糖皮质激素抵抗患者的状态。由于其对下丘脑-垂体-肾上腺（HPA）轴的刺激作用，RU 486作为抗糖皮质激素的慢性应用受限。迄今为止，仅推荐将RU 486应用于患有异位促肾上腺皮质激素（ACTH）分泌或肾上腺癌且对其他治疗无反应的无法手术的患者。该药物异常长的半衰期也给在治疗范围内滴定其剂量带来了问题。因此，开发一种短效、选择性糖皮质激素拮抗剂是未来研究的一个理想目标。
