Tomlinson Jeremy W, Walker Elizabeth A, Bujalska Iwona J, Draper Nicole, Lavery Gareth G, Cooper Mark S, Hewison Martin, Stewart Paul M
Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
Endocr Rev. 2004 Oct;25(5):831-66. doi: 10.1210/er.2003-0031.
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
11β-羟类固醇脱氢酶1型（11β-HSD1）可使无活性的可的松与活性皮质醇相互转换。虽然这种转换是双向的，但在体内它被认为起着还原酶的作用，在受体前水平生成活性糖皮质激素，增强糖皮质激素受体的激活。在这篇综述中，我们讨论了11β-HSD1的遗传学和酶学特征，并以组织特异性的方式描述了它在生理和病理中的作用。已明确了人类中可的松还原酶缺乏症的分子基础，即假定的“11β-HSD1基因敲除状态”，它是由HSD11B1基因内含子突变导致基因转录减少，以及己糖-6-磷酸脱氢酶突变引起的，己糖-6-磷酸脱氢酶是一种腔内酶，为11β-HSD1提供还原型烟酰胺腺嘌呤二核苷酸磷酸作为辅酶以允许其还原酶活性。我们推测，己糖-6-磷酸脱氢酶活性以及因此的还原型烟酰胺腺嘌呤二核苷酸磷酸供应，可能在决定11β-HSD1活性的方向性方面至关重要。对肥胖症和代谢综合征患者以及青光眼和骨质疏松症患者进行11β-HSD1还原酶活性的治疗性抑制，仍然是一个令人兴奋的前景。
