Type 1 11 β-hydroxysteroid Dehydrogenase as Universal Drug Target in Metabolic Diseases?

Abstract

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.

Discovery of Adamantyl Ethanone Derivatives as Potent 11β‐Hydroxysteroid Dehydrogenase Type 1 (11β‐HSD1) Inhibitors

“…[31] Inhibition of tissue-specific glucocorticoid action by regulating 11b-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases and therefore has attracted considerable attention over the last few years. [13,[32][33][34][35] Increased research efforts by the pharmaceutical industry have led to the discovery of numerous types of potent, selective 11b-HSD1 inhibitors, and the progress in this area has been recently reviewed. [35][36][37][38][39][40] Compounds 3-7 are examples of potent 11b-HSD1 inhibitors on which advanced preclinical studies or clinical studies have been performed.…”

Epimerase activity of the human 11β-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids

“…11␤-HSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and type 2 diabetes. Numerous studies have been devoted to finding potent 11␤-HSD1 inhibitors among natural and chemical molecules [13][14][15][16][17]. It is also possible that steroid molecules naturally produced in the organism Epiandrosterone (EpiA) derives from testosterone and is a substrate for CYP-7B1 (2) producing 7␣-hydroxy-EpiA which is then interconverted into 7␤-hydroxy-EpiA by 11␤-hydroxysteroid dehydrogenase type 1 (3).…”

Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Enzyme in the Liver in Fructose Induced Metabolic Syndrome Rat Model

“…Both these enzymes are involved in the interconversion of active glucocorticoid to inactive glucocorticoid. Glucocorticoid hormones involved in stress adaptation, metabolism regulation and response to inflammation (Opperman 2006). The differences between these two isozymes are the co-factors, affinity and reaction of conversion (Draper & Stewart 2005).…”

“…The 11β-HSD1 enzyme is widely distributed and dependent on nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. This enzyme has bi-directional action which acts as reductase (11β-OR) and dehydrogenase (11β-DH) (Opperman 2006). However, the function as 11β-OR is more dominant compared to 11β-DH.…”