11beta-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action.
Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1 and 11beta-HSD2) catalyse the interconversion of hormonally active cortisol and inactive cortisone. The enzyme evolved from a metabolic pathway to a novel mechanism underpinning human disease with the elucidation of the role of the type 2 or 'kidney' isozyme and an inherited form of hypertension, 'apparent mineralocorticoid excess'. 'Cushing's disease of the kidney' arises because of a failure of 11beta-HSD2 to inactivate cortisol to cortisone resulting in cortisol-induced mineralocorticoid excess.Conversely, 11beta-HSD1 has been linked to human obesity and insulin resistance, but also to other diseases in which glucocorticoids have historically been implicated (osteoporosis, glaucoma). Here, the activation of cortisol from cortisone facilitates glucocorticoid hormone action at an autocrine level. The molecular basis for the putative human 11beta-HSD1 'knockout'--'cortisone reductase deficiency'--has recently been described, an observation that also answers a long standing conundrum relating to the set-point of 11beta-HSD1 activity. In each case, these clinical studies have been underpinned by studies in vitro and the manipulation of enzyme expression in vivo using recombinant mouse models.
Draper
Nicole
N
Division of Medical Sciences, Institute of Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Stewart
Paul M
PM
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D003348:Cortisone / Q000378:metabolism*; D005901:Glaucoma / Q000201:enzymology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009765:Obesity / Q000201:enzymology; D010024:Osteoporosis / Q000201:enzymology
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D042842:11-beta-Hydroxysteroid Dehydrogenases; D003348:Cortisone; D006854:Hydrocortisone