Molecular Mechanisms of Human Hypertension

Mechanisms involved in the side effects of glucocorticoids

Mineralocorticoid receptors, both when in tissue extracts and when recombinant-derived, have equal affinity for the physiological mineralocorticoid aldosterone and for the glucocorticoids cortisol and corticosterone, which circulate at much higher concentrations than aldosterone. Such receptors are found in physiological mineralocorticoid target tissues (kidney, parotid, and colon) and in nontarget tissues such as hippocampus and heart. In mineralocorticoid target tissues the receptors are selective for aldosterone in vivo because of the presence of the enzyme 11 beta-hydroxy-steroid dehydrogenase, which converts cortisol and corticosterone, but not aldosterone, to their 11-keto analogs. These analogs cannot bind to mineralocorticoid receptors.

https://science.sciencemag.org/content/sci/242/4878/583.full.pdf

Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated

LOCALISATION OF 11β-HYDROXYSTEROID DEHYDROGENASE—TISSUE SPECIFIC PROTECTOR OF THE MINERALOCORTICOID RECEPTOR

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.

R. Valentino

Papers

Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age

17 Liquorice Induced Mineralocorticoid Excess: 11 ??- Hydroxysteroid Dehydrogenase Deficiency Comes of Age