BINDING OF PROGESTINS TO THE GLUCOCORTICOID RECEPTOR - CORRELATION TO THEIR GLUCOCORTICOID-LIKE EFFECTS ON INVITRO FUNCTIONS OF HUMAN MONONUCLEAR LEUKOCYTES
BINDING OF PROGESTINS TO THE GLUCOCORTICOID RECEPTOR - CORRELATION TO THEIR GLUCOCORTICOID-LIKE EFFECTS ON INVITRO FUNCTIONS OF HUMAN MONONUCLEAR LEUKOCYTES
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DOI：
10.1016/0006-2952(83)90474-4
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发表时间：
1983-01-01
影响因子：
5.8
通讯作者：
ANDERSSON, LC
中科院分区：
文献类型：
--
作者：
KONTULA, K;PAAVONEN, T;ANDERSSON, LC
测试了一些生理和合成孕激素与[~3H]地塞米松竞争与人单核白细胞糖皮质激素受体结合的能力，以及它们在同一细胞上诱导糖皮质激素样效应的能力。与参考化合物地塞米松(相对受体结合亲和力为100%)相比，具有孕烷型结构的两种有效的合成孕酮，甲地孕酮和甲羟孕酮对受体显示出相当大的结合亲和力(分别为46%和42%)。天然配体皮质醇与受体的相对结合亲和力明显较低(25%)。直接结合研究证实了乙酸甲羟孕酮与糖皮质激素受体的有效结合。根据使用孕激素受体特异性配体[~3H]Org2058[16.alpha.-16-ethyl-21-hydroxy-19-norpregn-4-ene-3，20-dione]的竞争实验结果，没有证据表明人单核白细胞中存在特定的孕激素受体。甲羟孕酮和甲地孕酮对淋巴细胞功能的影响。这些措施包括抑制T细胞有丝分裂原刀豆蛋白A和植物血凝素的增殖反应，以及在商陆有丝分裂原刺激的培养中促进免疫球蛋白分泌细胞的积累。孕激素的作用似乎是通过T淋巴细胞的辐射敏感(抑制)亚群来调节的。在结构上与19-去甲睾酮、去甲孕酮和去甲孕酮相关的合成孕激素几乎不与糖皮质激素受体结合，也不会对体外淋巴细胞功能产生明显影响。临床上常用的某些孕激素可能具有固有的糖皮质激素活性，有人建议，当这些化合物以药理剂量使用时，可归因于这一特征的副作用(例如，抑制垂体-肾上腺轴)可能是预期的。
A number of physiological and synthetic progestins were tested for their ability to compete with [3H]dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid-like effects on the same cells. As compared to the reference compound dexamethasone (relative receptor binding affinity defined as 100%), 2 potent synthetic progestins with a pregnane-type structure, megestrol acetate and medroxyprogesterone acetate, displayed a considerable binding affinity towards the receptor (46 and 42%, respectively). The relative binding affinity of the naturally occurring ligand, cortisol, to the receptor was clearly lower (25%). The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid. No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor-specific ligand [3H]Org 2058 [16.alpha.-16-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione] was used. Medroxyprogesterone acetate and megestrol acetate induced glucocorticoid-like effects on the lymphocyte functions. These included inhibition of the proliferative responses to the T-cell mitogens concanavalin A and phytohemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen-stimulated cultures. The progestin effect appears to be mediated through a radiosensitive (suppressor) subpopulation of T lymphocytes. The synthetic progestins related structurally to 19-nortestosterone, norethisterone and d-norgestrel, were virtually devoid of binding affinity towards the glucocorticoid receptor, nor did they measurably influence the in vitro lymphocyte functions. Certain progestins in common clinical use probably possess inherent glucocorticoid activity and it is suggested that side effects attributable to this character (e.g., suppression of the pituitary-adrenal axis) might be expected when these compounds are used in pharmacological doses.