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The enzyme 11β-HSD interconverts the active glucocorticoid cortisol and cortisone, an inactive
metabolite (Figure 1a). By the oxidation of cortisol to cortisone, 11β-HSD prevents glucocorticoids
from deleterious actions in certain cell types. For example, excess glucocorticoids in Leydig cells inhibit
testosterone synthesis [3,11]. Expression of 11β-HSD in Leydig cells prevents this effect of
glucocorticoids. In this way, 11β-HSD is important in androgen action. The enzyme 11β-HSD is also
important in aldosterone action in the distal tubule of the kidney. Glucocorticoids have high affinity for
the mineralocorticoid receptor [12] and can stimulate the mineralocorticoid response—uptake of sodium
from urine—one effect of which is to increase blood pressure. Local expression of 11β-HSD in the
distal tubule prevents this effect of glucocorticoids. The steroid aldosterone, which is not metabolized by
11β-HSD, can bind to the mineralocorticoid receptor and regulate sodium and potassium balance. Thus,
11β-HSD has an important role in regulating the biological actions of both glucocorticoids and
mineralocorticoids.
As would be expected, interference with 11β-HSD activity due to a mutation [13,14] or by an inhibitor
such as licorice (Figure 2) [1–3,15] has a variety of physiological effects including high blood pressure
due to mineralocorticoid actions of glucocorticoids in the kidney's distal tubule. Thus, studies to unravel
genetic hypertension in children and the actions of aldosterone in the kidney yielded the general insight
that, at specific times, altered expression of 11β-HSD in specific tissues is an important mechanism for
regulating glucocorticoid, mineralocorticoid, and androgen action.
A similar mechanism has been found for 17β-hydroxysteroid dehydrogenase (17β-HSD), the enzyme
that regulates the concentrations of estradiol and testosterone in human [5,16,17] (Figure 1b). Genetics
diseases associated with mutations in this enzyme lead to developmental abnormalities [18]. Enzymes
that regulate the concentrations of retinoids [19] and prostaglandins [20] may also have a similar role
[6].
B. Multiple Divergent 11β-Hydroxysteroid and 17β-Hydroxysteroid Dehydrogenases
The cloning and sequencing of 11β-HSD [21–25] and 17β-HSD [16–18,26] revealed two 11β-HSDs and
four 17β-HSDs with very different sequences
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