Harris A W, Baxter J D
Monogr Endocrinol. 1979;12:423-48. doi: 10.1007/978-3-642-81265-1_23.
The spectrum of physiological, pathological, and genetic variations in sensitivity to glucocorticoids is reviewed. The receptor for these hormones is common to most mammalian tissues, and yet the responses are widely divergent. Although there may be differences in the receptors to account for some of this diversity, it is likely that it is largely due to cellular programming not involving the receptors. In addition to the intertissue differences in sensitivity, it is also clear that intra-tissue differences occur. The greatest amount of information has been accumulated with lymphoid cell systems and there are sensitivity differences to specific responses such as cell killing or effects on immunological functions. In these systems, there can be major variations in either the extent of the response (e. g., from mild growth inhibition to cellular killing) or whether any effect is observed. Further, dose requirements for certain responses can vary by several orders of magnitude. Within a given tissue there may be developmental changes in sensitivity that are not due to obvious changes in the receptor, and decreased sensitivity with aging that in some cases has been associated with changes in receptor binding activity. Finally, the cellular sensitivity can either be influenced by hormones and other factors that affect the ability of the glucocorticoid to elicit a particular response (in a synergistic or antagonistic manner), or the same function regulated by the glucocorticoid can be inducible by the steroid, appearing some time after administration of the steroid and disappearing after steroid removal. Genetic variations in sensitivity to glucocorticoids also occur. In humans these may be generalized, affecting glucocorticoid action in all responsive tissues, and could be important in the pathogenesis of certain diseases. Perhaps the most striking genetic alterations, however, are observed in cultured lymphoid and fibroblastic cells and in acute lymphoblastic leukaemia cells ordinarily growth inhibited or killed by the glucocorticoid. Mutant cell lines arise that are highly resistant and most of these have abnormalities in the glucocorticoid receptor. In some cases binding activity is totally lost, easily expalining the resistance. In other cases, there is a more modest reduction in binding or a change in receptor properties that give it increased or decreased nuclear and DNA binding activity. An analysis of these cell lines suggests that many of the defects are in some receptor property presently not understood that makes the receptor ineffective rather than the defect being due to the quantitative changes in receptor levels detected. The frequency of emergence of steroid-resistant cells can vary widely from about 10(-5) in S49 cells to less than 10(-8) in certain thymic cell lines...
本文综述了糖皮质激素敏感性在生理、病理和遗传方面的变化范围。这些激素的受体在大多数哺乳动物组织中普遍存在，但反应却大不相同。尽管受体可能存在差异以解释部分这种多样性，但很可能主要是由于不涉及受体的细胞编程所致。除了组织间的敏感性差异外，组织内差异也很明显。关于淋巴细胞系统积累的信息最多，并且在诸如细胞杀伤或对免疫功能的影响等特定反应方面存在敏感性差异。在这些系统中，反应程度（例如，从轻度生长抑制到细胞杀伤）或是否观察到任何效应都可能存在重大差异。此外，某些反应的剂量要求可能相差几个数量级。在给定组织内，敏感性可能存在发育变化，这并非由于受体的明显变化引起，并且随着年龄增长敏感性降低，在某些情况下这与受体结合活性的变化有关。最后，细胞敏感性可受到激素和其他影响糖皮质激素引发特定反应能力的因素（以协同或拮抗方式）的影响，或者糖皮质激素调节的相同功能可由类固醇诱导，在给予类固醇一段时间后出现，类固醇去除后消失。对糖皮质激素的敏感性也存在遗传变异。在人类中，这些变异可能是全身性的，影响所有反应性组织中的糖皮质激素作用，并且在某些疾病的发病机制中可能很重要。然而，最显著的遗传改变可能是在培养的淋巴细胞和成纤维细胞以及通常被糖皮质激素抑制生长或杀死的急性淋巴细胞白血病细胞中观察到的。出现了高度耐药的突变细胞系，其中大多数在糖皮质激素受体方面存在异常。在某些情况下，结合活性完全丧失，这很容易解释耐药性。在其他情况下，结合能力有更适度的降低或受体特性发生变化，导致其核结合和DNA结合活性增加或降低。对这些细胞系的分析表明，许多缺陷存在于目前尚不清楚的某些受体特性中，这使得受体无效，而不是缺陷归因于所检测到的受体水平的定量变化。类固醇耐药细胞出现的频率差异很大，从S49细胞中的约10^(-5)到某些胸腺细胞系中的不到10^(-8)……
