Schäcke Heike, Döcke Wolf Dietrich, Asadullah Khusru
Research Business Area Dermatology, Schering AG, D-13342, Berlin, Germany.
Pharmacol Ther. 2002 Oct;96(1):23-43. doi: 10.1016/s0163-7258(02)00297-8.
Glucocorticoids (GCs) represent the most important and frequently used class of anti-inflammatory drugs. While the therapeutic effects of GCs have been known and used for more than 50 years, major progress in discovering the underlying molecular mechanisms has only been made in the last 10-15 years. There is consensus that the desired anti-inflammatory effects of GCs are mainly mediated via repression of gene transcription. In contrast, the underlying molecular mechanisms for GC-mediated side effects are complex, distinct, and frequently only partly understood. Recent data suggest that certain side effects are predominantly mediated via transactivation (e.g., diabetes, glaucoma), whereas others are predominantly mediated via transrepression (e.g., suppression of the hypothalamic-pituitary-adrenal axis). For a considerable number of side effects, the precise molecular mode is either so far unknown or both transactivation and transrepression seem to be involved (e.g., osteoporosis). The differential molecular regulation of the major anti-inflammatory actions of GCs and their side effects is the basis for the current drug-finding programs aimed at the development of dissociated GC receptor (GR) ligands. These ligands preferentially induce transrepression by the GR, but only reduced or no transactivation. This review summarizes the current knowledge of the most important GC-mediated side effects from a clinical to a molecular perspective. The focus on the molecular aspects should be helpful in predicting the potential advantages of selective GR agonists in comparison to classical GCs.
糖皮质激素（GCs）是最重要且最常用的一类抗炎药物。虽然GCs的治疗作用已为人所知并应用了50多年，但在揭示其潜在分子机制方面的重大进展仅在过去10至15年才取得。人们普遍认为，GCs预期的抗炎作用主要是通过基因转录的抑制来介导的。相比之下，GC介导的副作用的潜在分子机制复杂、独特，且往往仅被部分理解。最近的数据表明，某些副作用主要是通过反式激活介导的（如糖尿病、青光眼），而其他副作用则主要是通过反式抑制介导的（如下丘脑-垂体-肾上腺轴的抑制）。对于相当多的副作用，其精确的分子模式要么至今未知，要么似乎反式激活和反式抑制都有涉及（如骨质疏松症）。GCs主要抗炎作用及其副作用的差异分子调控是当前旨在开发解离型糖皮质激素受体（GR）配体的药物研发项目的基础。这些配体优先诱导GR的反式抑制，但仅减少或不诱导反式激活。本综述从临床到分子层面总结了目前关于最重要的GC介导的副作用的知识。关注分子层面有助于预测选择性GR激动剂相对于经典GCs的潜在优势。
