Enzymology and molecular biology of glucocorticoid metabolism in humans.
Glucocorticoids (GCs) are a vital class of steroid hormones that are secreted by the adrenal cortex and that are regulated by ACTH largely under the control of the hypothalamic-pituitary-adrenal axis. GCs mediate profound and diverse physiological effects in vertebrates, ranging from development, metabolism, neurobiology, anti-inflammation and programmed cell death to many other fuctions. Multiple factors "downstream" of GC secretion, such as glucocorticoid receptor (GR) number and the abundance of plasma binding proteins have originally been considered as modulators of GC action. However, in the last decade the role of tissue-specific GC activating and inactivating enzymes have been identified as additional determinants in GC signalling pathways. On the cellular level, they function as important pre-receptor regulators by acting as "molecular switches" for receptor-active and receptor-inactive GC hormones. According to their biologic activity to catalyze the interconversion of C11-hydroxyl and C11-oxo GCs these enzymes have been named 11beta-hydroxysteroid dehydrogenase (11beta-HSD; EC 1.1.1.146). Two isoforms of 11beta-HSD have been cloned and characterized so far. 11beta-HSD type 1 is found in a wide range of tissues, acts predominantly as a reductase in intact cells and tissues by regenerating active cortisol from cortisone, and has been described to regulate GC access to the GR. 11beta-HSD type 2 is found mainly in mineralocorticoid target tissues such as kidney and colon, acts only as a dehydrogenase by producing inactive cortisone, and has been found to protect the mineralocorticoid receptor from high levels of receptor-active cortisol. Recently, 11beta-HSD 1 has become highly topical due to the finding that 11beta-HSD 1 plays a pivotal role in the pathogenesis of central obesity and the appearance of the metabolic syndrome. This review provides an overview on the components involved in GC signalling of 11beta-HSD type 1 as an important pre-receptor control enzyme that modulates activation of the GR.
Blum
Andreas
A
Institute of Experimental Toxicology, Universitats Klinikum Schleswig-Holstein, Campus Kiel, Brunswiker Strasse 10, D-24105 Kiel, Germany.
Maser
Edmund
E
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D043204:Mineralocorticoid Excess Syndrome, Apparent / Q000201:enzymology / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism
D005938:Glucocorticoids; D007527:Isoenzymes; D011965:Receptors, Glucocorticoid; D042842:11-beta-Hydroxysteroid Dehydrogenases