Edwards D P, Altmann M, DeMarzo A, Zhang Y, Weigel N L, Beck C A
Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.
J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):449-58. doi: 10.1016/0960-0760(95)00091-d.
Currently available progesterone antagonists have been suggested to fall into two categories based on differences in how they interact with and inactivate the progesterone receptor (PR). The anti-progestin ZK98299 (Type I) impairs PR association with DNA, while Type II compounds (RU486, ZK112993, ZK98734) promote PR binding to DNA. Type II agents, therefore, appear to inhibit receptor activity at a step downstream of DNA binding, presumably failing to induce conformational changes in PR structure requird for enhancement of transcription. This paper discusses both published and unpublished data supporting the concept of two types of progestin antagonists. Using PR-mediated induction of reporter genes in breast cancer cells as an assay for biological response, both types of anti-progestins, after correction for difference in steroid binding affinity, inhibit progestin induction substoichiometrically. However, Type II anti-progestins are more potent, inhibiting at lower ratios of antagonist to agonist than ZK98299. This suggests that in addition to behaving by classical competitive mechanisms these compounds (in particular Type II) may exhibit additional activity as transrepressors of PR in the same cell bound to hormone agonist. Transrepression may occur by the combined mechanisms of heterodimerization and competition for binding to DNA. In support of this, mixed ligand dimers form readily in solution between a PR subunit bound to agonist and another bound to either type of anti-progestin, whereas these mixed ligand dimers bind poorly, if at all, to specific progesterone response elements (PREs) in vitro. Additionally, when added as a single ligand, Type II agents increase PR dimerization in solution and PR affinity for PREs as compared with single ligand dimers formed by progestin agonist. This contrasts with ZK98299, when given as a single ligand, which reduces PR affinity for PREs without disrupting solution dimerization. Thus the higher affinity of PR for PREs may account for the greater biological potency of Type II compounds as compared with ZK98299. As a further distinction between types of antiprogestins, ZK98299 minimally stimulates phosphorylation of PR whereas RU486 increases site-specific phosphorylation of PR in a manner indistinguishable from that of hormone agonist. Additionally, ZK98299 is not susceptible in vivo to functional switching to a partial agonist by cross talk with cAMP signal transduction pathways, as occurs with Type II compounds. Thus, ZK98299 under certain conditions may be a more pure antagonist than Type II compounds.
目前可用的孕酮拮抗剂根据其与孕酮受体（PR）相互作用及使其失活方式的不同，被认为可分为两类。抗孕激素ZK98299（I型）会损害PR与DNA的结合，而II型化合物（RU486、ZK112993、ZK98734）则促进PR与DNA的结合。因此，II型药物似乎在DNA结合的下游步骤抑制受体活性，推测无法诱导PR结构发生增强转录所需的构象变化。本文讨论了支持两种类型孕酮拮抗剂概念的已发表和未发表的数据。以PR介导的乳腺癌细胞中报告基因的诱导作为生物反应的检测方法，在对类固醇结合亲和力的差异进行校正后，两种类型的抗孕激素均以亚化学计量方式抑制孕激素诱导。然而，II型抗孕激素的效力更强，与ZK98299相比，在拮抗剂与激动剂的比例较低时就能产生抑制作用。这表明，除了通过经典的竞争机制发挥作用外，这些化合物（特别是II型）可能作为与激素激动剂结合在同一细胞中的PR的反式抑制剂表现出额外的活性。反式抑制可能通过异源二聚化和竞争结合DNA的联合机制发生。支持这一点的是，在溶液中，与激动剂结合的PR亚基和与任何一种抗孕激素结合的另一个亚基之间很容易形成混合配体二聚体，而这些混合配体二聚体在体外与特定的孕酮反应元件（PREs）结合很差，甚至根本不结合。此外，与孕激素激动剂形成的单配体二聚体相比，当作为单配体添加时，II型药物会增加溶液中PR的二聚化以及PR对PREs的亲和力。这与作为单配体给药时的ZK98299形成对比，ZK98299会降低PR对PREs的亲和力但不破坏溶液中的二聚化。因此，与ZK98299相比，PR对PREs的更高亲和力可能解释了II型化合物更强的生物学效力。作为抗孕激素类型之间的另一个区别，ZK98299对PR磷酸化的刺激作用最小，而RU486以与激素激动剂无法区分的方式增加PR的位点特异性磷酸化。此外，ZK98299在体内不会像II型化合物那样通过与cAMP信号转导途径的串扰而功能转变为部分激动剂。因此，在某些条件下，ZK98299可能比II型化合物更纯粹的拮抗剂。
