Abstract
The 11β-hydroxysteroid dehydrogenases (11β-HSDs) play a pivotal role in glucocorticoid
(GC) action. 11β-HSD1 is a predominant reductase, activating GCs from inert metabolites,
whereas 11β-HSD2 is a potent dehydrogenase inactivating GCs. Knowing the metabolic
effects of GCs, a selective inhibition of 11β-HSD1 represents a potential target for
therapy of impaired glucose tolerance, insulin insensitivity and central obesity.
In vitro, 11β-HSD1 is selectively inhibited by chenodesoxycholic acid (CDCA) and upregulated
under GC exposure. Therefore, we aimed to investigate the effects of CDCA and prednisolone
on hepatic 11β-HSD1 activity in vivo by measuring 11-reduction of orally given cortisone
(E) acetate to cortisol (F). CDCA or placebo was given to 5 male healthy volunteers
within a randomised cross-over trial before and after oral administration of 12.5 mg
E acetate at 8:00 h. For measurement of in vivo effects of GCs on 11β-HSD1 activity,
hepatic reduction of 25 mg E acetate before and after treatment with prednisolone
(30 mg for 6 days) was determined in 7 healthy males. Serum GC levels were determined
using a fully automated liquid chromatographic system. CDCA had no effect on the activity
of 11β-HSD1 in vivo. Prednisolone therapy leads to a marked rise in serum F concentrations
and an elevated F/E serum ratio. This proves GC-induced activation of hepatic 11β-HSD1,
which could not be extinguished by a parallel increase of IGF-1 under prednisolone.
CDCA does not affect in vivo activity of 11β-HSD1 when given in therapeutic dosages.
During GC treatment, increased hepatic activation of E to F may aggravate metabolic
side effects of GCs such as seen in the metabolic syndrome.
Key words
metabolism - selective inhibition - glucocorticoids - metabolic syndrome - IGF-1
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Correspondence
S. Diederich
Endokrinologikum Berlin am
Gendarmenmarkt
Centre for Endocrine and
Metabolism Diseases
Friedrichstraße 76 (Q207)
10117 Berlin
Phone: +49/30/2091 562 290
Fax: +49/30/2091 562 291
Email: sven.diederich@endokrinologikum.com
