School of Clinical and Experimental Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston B15 2TH, United Kingdom.
Endocr Rev. 2013 Aug;34(4):525-55. doi: 10.1210/er.2012-1050. Epub 2013 Apr 23.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.
11β-羟类固醇脱氢酶 1 型（11β-HSD1）可将无活性的糖皮质激素可的松及其活性形式皮质醇相互转化。它广泛表达，尽管是双向的，但在体内主要作为氧化还原酶发挥作用，产生活性糖皮质激素。这使得糖皮质激素受体的激活可以在组织特异性的受体前水平受到调节。在这篇综述中，我们将讨论 11β-HSD1 的酶学和分子生物学以及皮质酮还原酶缺乏症的分子基础。我们还将讨论 11β-HSD1 活性的改变如何与许多疾病状态有关，并探讨其在不同组织的生理学和病理学中的作用。最后，我们将讨论目前正在开发的选择性 11β-HSD1 抑制剂的现状，并在代谢综合征患者的 II 期试验中进行测试。尽管数据尚属初步，但 11β-HSD1 的治疗性抑制也是治疗骨质疏松症、青光眼、颅内高压和认知能力下降等多种其他疾病的令人兴奋的前景。
