Two
isoforms of
11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active
glucocorticoid,
cortisol, and inactive
cortisone.
11beta-HSD1 acts predominantly as an oxo-
reductase in vivo using
NADP(H) as a cofactor to generate
cortisol. In contrast,
11beta-HSD2 is a
NAD-dependent
dehydrogenase inactivating
cortisol to
cortisone, thereby protecting the
mineralocorticoid receptor from occupation by
cortisol. In peripheral tIssues, both
enzymes serve to control the availability of
cortisol to bind to
corticosteroid receptors.
11beta-HSD2 protects the
mineralocorticoid receptor from
cortisol excess; mutations in the HSD11B2 gene explain an inherited form of
hypertension, the syndrome of 'apparent
mineralocorticoid excess', in which '
Cushing's disease of the kidney' results in
cortisol-mediated
mineralocorticoid excess. Inhibition of
11beta-HSD2 explains the
mineralocorticoid excess state seen following liquorice ingestion and more subtle defects in
enzyme expression might be involved in the pathogenesis of '
essential' hypertension.
11beta-HSD1 by generating
cortisol in an autocrine fashion facilitates
glucocorticoid receptor-mediated action in key peripheral tIssues including liver, adipose tissue, bone and the eye. '
Cushing's disease of the omentum' has been proposed as an underlying mechanism in the pathogenesis of
central obesity and raises the exciting possibility of selective
11beta-HSD1 inhibition as a novel
therapy for patients with the
metabolic syndrome. 'Pre-receptor' metabolism of
cortisol via 11beta-HSD
isozymes is an important facet of
corticosteroid hormone action. Aberrant expression of these
isozymes is involved in the pathogenesis of diverse human diseases including
hypertension,
insulin resistance and
obesity. Modulation of
enzyme activity may offer a future therapeutic approach to treating these diseases whilst circumventing the endocrine consequences of
glucocorticoid excess or deficiency.