title: 11β-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects.
abstract: 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.
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston B15 2TH, United Kingdom.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Gathercole
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Morgan
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cooper
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Sinclair
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015507:Drugs, Investigational / Q000627:therapeutic use; D004702:Endocrine Glands / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004700:Endocrine System Diseases / Q000188:drug therapy / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D014644:Genetic Variation; D006801:Humans; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology; D057170:Translational Research, Biomedical
chemical_list: D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human