Oppermann Udo
Structural Genomics Consortium, University of Oxford, Oxford, OX3 7LD, UK.
Endocr Metab Immune Disord Drug Targets. 2006 Sep;6(3):259-69. doi: 10.2174/187153006778250000.
Glucocorticoid hormones play essential roles in adaptation to stress, regulation of metabolism and inflammatory responses. Their effects primarily depend on their binding to intracellular receptors leading to altered target gene transcription as well as on cell-type specific biotransformation between 11beta-hydroxy glucocorticoids and their 11-oxo metabolites. The latter effect is accomplished by two different 11beta-hydroxysteroid dehydrogenase isozymes, constituting a shuttle system between the receptor ligand cortisol and its non-binding precursor cortisone. Whereas the type 1 enzyme (11beta-HSD1) is in vitro a NADP(H)- dependent bidirectional enzyme, it reduces in most instances in vivo cortisone to active cortisol. The type 2 enzyme is an exclusive NAD+ dependent dehydrogenase of glucocorticoids, thus "protecting" the mineralocorticoid receptor against illicit occupation by cortisol. Inhibition of tissue-specific glucocorticoid activation by 11beta-HSD1 constitutes a promising target in the treatment of metabolic and cardiovascular diseases. Pharmacological inhibition leads in animal models to lowered hepatic glucose production and increased insulin sensitivity, the primary goals in therapy of diabetes mellitus. Importantly, 11beta-HSD1 activity appears to be intrinsically linked to all features of the metabolic syndrome, which could at least in animal experiments be modulated by use of synthetic selective inhibitors. Importantly, these features include not only insulin resistance but also dyslipidemia, obesity and arterial hypertension. Animal studies and pharmacological experiments suggest further unrelated target areas, for example improvement of cognitive function and treatment of glaucoma, due to the role of glucocorticoids and cellular activation by 11beta-HSD1 in these pathologies. The recent development of specific 11beta-HSD1 inhibitors coupled with advances on structural knowledge and regulation of the 11beta-HSD1 target has undoubtedly promoted the understanding of glucocorticoid control of metabolic regulation. Taken together, it appears that inhibitors against 11beta-HSD1 constitute a promising avenue for novel treatment strategies against the underlying causes of cardiovascular and other metabolic diseases.
糖皮质激素在应激适应、代谢调节和炎症反应中发挥着重要作用。它们的作用主要取决于与细胞内受体的结合，从而导致靶基因转录改变，以及11β-羟基糖皮质激素与其11-氧代代谢产物之间的细胞类型特异性生物转化。后一种作用是由两种不同的11β-羟基类固醇脱氢酶同工酶完成的，它们构成了受体配体皮质醇与其非结合前体可的松之间的穿梭系统。虽然1型酶（11β-HSD1）在体外是一种依赖NADP（H）的双向酶，但在大多数情况下，它在体内会将可的松还原为活性皮质醇。2型酶是一种专门的依赖NAD+的糖皮质激素脱氢酶，因此“保护”盐皮质激素受体不被皮质醇非法占据。抑制11β-HSD1介导的组织特异性糖皮质激素激活是治疗代谢性和心血管疾病的一个有前景的靶点。在动物模型中，药物抑制可降低肝脏葡萄糖生成并提高胰岛素敏感性，这是糖尿病治疗的主要目标。重要的是，11β-HSD1活性似乎与代谢综合征的所有特征内在相关，至少在动物实验中，使用合成选择性抑制剂可以对其进行调节。重要的是，这些特征不仅包括胰岛素抵抗，还包括血脂异常、肥胖和动脉高血压。动物研究和药理实验表明，由于糖皮质激素和11β-HSD1在这些病理过程中的作用，还有其他不相关的靶点领域，例如改善认知功能和治疗青光眼。最近特异性11β-HSD1抑制剂的开发，以及在11β-HSD1靶点的结构知识和调节方面的进展，无疑促进了对糖皮质激素代谢调节控制的理解。综上所述，针对11β-HSD1的抑制剂似乎是针对心血管和其他代谢疾病潜在病因的新型治疗策略的一个有前景的途径。
