PubMed · 16776239
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Isamu Miyamori. 2006-05-28. [Cellular function of 11beta-HSD1].. https://pubmed.ncbi.nlm.nih.gov/16776239/
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Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Glucocorticoid action within the cells is regulated by the levels of glucocorticoid receptor (GR) expression and two enzymes, 11-beta hydroxysteroid dehydrogenase type 1 (11betaHSD1), which converts inactive to active glucocorticoids, and 11-beta hydroxysteroid dehydrogenase type 2 (11betaHSD2), which regulates the access of active glucocorticoids to the receptor by converting cortisol/corticosterone to the glucocorticoid-inactive form cortisone/dehydrocorticosterone. Male Wistar rats developed obesity by being fed a high-fat diet for 56 days, and GR, 11betaHSD1 and 11betaHSD2 gene expression were compared with control-diet fed animals. Gene expression analysis of 11betaHSD1, 11betaHSD2 and GR were performed by RT-PCR in subcutaneous and retroperitoneal adipose tissue. High-fat fed animals overexpressed 11betaHSD2 in subcutaneous but not in retroperitoneal fat. Interestingly, mRNA levels strongly correlated in both tissues with different parameters related to obesity, such as body weight, adiposity and insulin resistance, suggesting that this gene is a reliable marker of adiposity in this rat model of obesity. Thus, 11betaHSD2 is expressed in adipose tissue by both adipocytes and stromal-vascular cells, which suggests that this enzyme may play an important role in preventing fat accumulation in adipose tissue.
The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts the inactive 11-dehydrocorticosterone into the active glucocorticoid corticosterone. There is accumulating evidence indicating widespread expression of 11beta-HSD1 in the brain. However, there is little information about regulation of 11beta-HSD1 expression in this tissue. Using in situ hybridization involving use of 35S-labeled cRNA probe, we have studied the distribution of cells expressing 11beta-HSD1 mRNA in the male mouse forebrain as well as the effects of adrenalectomy (ADX) and acute administration of corticosterone (3 and 24 h) on 11beta-HSD1 mRNA levels. Cells expressing 11beta-HSD1 mRNA were mostly detected in the cerebral cortex, hippocampus, amygdala and medial preoptic area, with the highest expression in the cerebral cortex (retrosplenial granular area) and hippocampus (CA3 and granular layer of the gyrus dentatus). Seven days following ADX, 11beta-HSD mRNA levels were increased by 50% in the gyrus dentatus, by 100% in the CA3 area, and 105% in the cerebral cortex. Administration of corticosterone to ADX mice induced a significant decrease in mRNA, in both the hippocampus and cerebral cortex so that, at the 24 h time interval, the levels were similar to those observed in intact mice. These results clearly indicate that circulating corticosterone is downregulating the expression of 11beta-HSD1 mRNA in the two forebrain areas studied. This downregulation might contribute to maintain low intracellular corticosterone levels in central regions and then prevent the deleterious effects induced by high glucocorticoid levels.