Disease relevance of 11-DEHYDROCORTICOSTERONE

• Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor [1].
• Carbenoxolone sodium, CS, a liquorice derivative associated with hypertension and sodium retention, has been demonstrated to inhibit 11 beta-hydroxysteroid dehydrogenase, an enzyme that metabolizes cortisol and corticosterone to their respective inactive 11-dehydro products (cortisone and 11-dehydrocorticosterone) [2].

High impact information on 11-DEHYDROCORTICOSTERONE

• This enzyme catalyses the conversion of the active glucocorticoids corticosterone and cortisol to inert 11 keto-products (11-dehydrocorticosterone, cortisone), thus regulating access of glucocorticoids to receptors [3].
• 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) intracellularly regenerates active corticosterone from circulating inert 11-dehydrocorticosterone (11-DHC) in specific tissues [4].
• 11 beta-Hydroxysteroid dehydrogenase in cultured hippocampal cells reactivates inert 11-dehydrocorticosterone, potentiating neurotoxicity [5].
• Metabolites of 11 beta-HSD1 (corticosterone or 11-dehydrocorticosterone) inhibited or increased pentose flux, respectively, demonstrating metabolic interconnectivity [6].
• In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone [7].

Biological context of 11-DEHYDROCORTICOSTERONE

• Incubation of beta-cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release, indicating cellular activation of 11-dehydrocorticosterone to the receptor ligand, further confirmed by reporter gene assays [8].
• The enzymatic reaction was unidirectional, oxidative, and inhibited by the product, 11-dehydrocorticosterone, with an IC50 of approximately 200 nM [9].
• Corticosterone and 11-dehydrocorticosterone stimulate Na,K-ATPase gene expression in vascular smooth muscle cells [10].
• Transfection of rat 11 beta-HSD1 cDNA into amphibian cells with a mineralocorticoid phenotype encodes 11 beta-reductase activity (activation of inert 11-dehydrocorticosterone) suggesting that 11 beta-HSD1 does not have the necessary properties to protect renal MRs from exposure to glucocorticoids [11].
• In addition, the three mutations had little effect on the binding of the rodent substrate 11-dehydrocorticosterone, suggesting that Y177 does not confer substrate specificity [12].

Anatomical context of 11-DEHYDROCORTICOSTERONE

• The relative potencies of thyroid hormones were T3 greater than T4 greater than rT3, and for corticosteroids, Dex much greater than corticosterone greater than 11-dehydrocorticosterone = cortisol greater than cortisone [13].
• Primary cultures of intact rat Leydig cells showed predominant 11beta-reductase activity, activating 50-70% of 11-dehydrocorticosterone to corticosterone over 3 h, whereas 11beta-dehydrogenation was <5% [14].
• The localization in the brain and metabolism of 3H-labeled corticosterone (B) and 11-dehydrocorticosterone (A) of high specific radioactivity was determined after stereotaxic injection into the hippocampus of anesthetized rats [15].
• When 5 x 10(-4) mol/L nicotinamide-adenine dinucleotide phosphate+ was added to sonicated fibroblasts, conversion increased to 50%, corresponding to 12 pmol 11-dehydrocorticosterone formed/mg protein [16].
• Liver, mesenteric and epididymal adipose tissue corticosterone and 11-dehydrocorticosterone concentrations as well as circulating corticosterone concentrations were measured [17].

Associations of 11-DEHYDROCORTICOSTERONE with other chemical compounds

• 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the interconversion of biologically inactive 11 keto derivatives (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone) in fat, liver, and other tissues [6].
• The extent of this action is determined by the numbers of GR within the Leydig cell, the intracellular concentration of glucocorticoid, and 11beta-hydroxysteroid dehydrogenase (11betaHSD) activities that interconvert corticosterone (in the rat) and its biologically inert derivative, 11-dehydrocorticosterone [18].
• 11 beta-OHSD activity in renal minces, assessed by the percent of corticosterone (10(-8) M) transformed to 11-dehydrocorticosterone (compound A), was significantly lower in the newborn kidney (newborn 45.7 +/- 3.8%, 8 day 70.2 +/- 3.8%, and adult 73.4 +/- 3.1%, P < 0.001 1 vs. 8 day) [19].
• We attempted to clone the putative 11-dehydrocorticosterone receptor by RT-PCR with two degenerate primers from highly homologous regions of the DNA and steroid binding domains of the receptor subfamily [20].
• Conversion of 11-dehydrocorticosterone to corticosterone did not occur in intact cells or in homogenates incubated with NADH or NADPH [21].

Gene context of 11-DEHYDROCORTICOSTERONE

• In mammalian tissues, at least two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone) [22].
• 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of biologically active cortisol to inactive cortisone in man, and corticosterone to 11-dehydrocorticosterone in rodents [23].
• 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive 11-dehydrocorticosterone into active corticosterone, thus amplifying glucocorticoid receptor-mediated tissue glucocorticoid action, particularly in the liver [24].
• Cells transfected with the 11 beta HSD-2 cDNA converted corticosterone into 11-dehydrocorticosterone [25].
• 11 Beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone [26].

Analytical, diagnostic and therapeutic context of 11-DEHYDROCORTICOSTERONE

• Afterwards, the amounts of 3H-B and of the metabolite 11-dehydrocorticosterone (3H-A) were determined using HPLC analysis [27].

References