Pharmacodynamics and pharmacokinetics of synthetic mineralocorticoids and glucocorticoids: receptor transactivation and prereceptor metabolism by 11beta-hydroxysteroid-dehydrogenases

Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme
S DiederichV Bähr

Abstract

Glucocorticoid (GC) and mineralocorticoid (MC) action in target tissues is determined by prereceptor metabolism by 11beta-hydroxysteroid-dehydrogenases (HSDs) and receptor transactivation. We characterized these parameters for steroids often used in clinical practice. HSD activity was examined in human liver (HSD1) and kidney microsomes (HSD2) and in CHO cells stably transfected with both enzymes. GC and MC transcriptional activity was tested by luciferase assay in CV-1 cells transfected with human GC or MC receptor expression vectors. The 11-hydroxy-group is necessary for GC and MC receptor transactivation. As HSD2 oxidizes 11-hydroxysteroids to inactive 11-dehydrosteroids, GC and MC activity in HSD2-expressing tissues (kidney, colon) is regulated by this enzyme. As 9alpha-fluorination (such as in 9alpha-fluorocortisol) decreases oxidation by HSD2 and increases both GC and MC receptor transactivation, this modification leads to optimal, but non-selective transactivation of both receptors. Increased GC receptor and decreased MC receptor transactivation leading to more selective GC activity is reached using the following substituents: 16beta-methyl (in betamethasone), 16alpha-methyl (in dexamethasone) and triangle up 1-dehydro-c...Continue Reading

Citations

Nov 13, 2012·Endocrinology·Zhonghua TangSeth Guller
Nov 7, 2007·European Journal of Endocrinology·Brian R Walker
Aug 12, 2009·Clinical Ophthalmology·Karim N Jamal, David G Callanan
Dec 20, 2008·Der Internist·C DodtF Sayk
Nov 3, 2005·American Journal of Physiology. Endocrinology and Metabolism·Mark R GarbrechtJeanne M Snyder
Jan 13, 2006·American Journal of Physiology. Renal Physiology·Sophie de SeigneuxSøren Nielsen
Nov 11, 2019·International Journal of Clinical Oncology·Giandomenico RovielloAlberto D'Angelo
Nov 24, 2016·Der Urologe. Ausg. A·H Kübler

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