The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation.

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Serval ID
serval:BIB_0BD272678931
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation.
Journal
Toxicological Sciences : An Official Journal of the Society of Toxicology
Author(s)
Fürstenberger C., Vuorinen A., Da Cunha T., Kratschmar D.V., Saugy M., Schuster D., Odermatt A.
ISSN
1096-0929 (Electronic)
ISSN-L
1096-0929
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
126
Number
2
Pages
353-361
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
Anabolic androgenic steroids (AAS) are testosterone derivatives used either clinically, in elite sports, or for body shaping with the goal to increase muscle size and strength. Clinically developed compounds and nonclinically tested designer steroids often marketed as food supplements are widely used. Despite the considerable evidence for various adverse effects of AAS use, the underlying molecular mechanisms are insufficiently understood. Here, we investigated whether some AAS, as a result of a lack of target selectivity, might inhibit 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2)-dependent inactivation of glucocorticoids. Using recombinant human 11β-HSD2, we observed inhibitory effects for several AAS. Whereas oxymetholone, oxymesterone, danazol, and testosterone showed medium inhibitory potential, fluoxymesterone was a potent inhibitor of human 11β-HSD2 (half-maximal inhibitory concentration [IC(50)] of 60-100nM in cell lysates; IC(50) of 160nM in intact SW-620, and 530nM in MCF-7 cells). Measurements with rat kidney microsomes and lysates of cells expressing recombinant mouse 11β-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11β-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11β-HSD2. Structural modeling revealed similar binding modes for fluoxymesterone and cortisol, supporting a competitive mode of inhibition of 11β-HSD2-dependent cortisol oxidation by this AAS. No direct modulation of mineralocorticoid receptor (MR) function was observed. Thus, 11β-HSD2 inhibition by fluoxymesterone may cause cortisol-induced MR activation, thereby leading to electrolyte disturbances and contributing to the development of hypertension and cardiovascular disease.
Keywords
11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors, Anabolic Agents/toxicity, Animals, Cell Line, Enzyme Inhibitors/pharmacology, Fluoxymesterone/toxicity, Glucocorticoids/antagonists & inhibitors, Humans, Mice
Pubmed
Web of science
Open Access
Yes
Create date
03/12/2012 15:53
Last modification date
25/09/2019 7:08
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