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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Fürstenberger Cornelia, Vuorinen Anna, Da Cunha Thierry, Kratschmar Denise V, Saugy Martial, Schuster Daniela, Odermatt Alex,
Project The Regulation of Glucocorticoid and Mineralocorticoid Hormone Action by 11beta-Hydroxysteroid Dehydrogenases
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Original article (peer-reviewed)

Journal Toxicological sciences : an official journal of the Society of Toxicology
Volume (Issue) 126(2)
Page(s) 353 - 61
Title of proceedings Toxicological sciences : an official journal of the Society of Toxicology
DOI 10.1093/toxsci/kfs022


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.