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

Article Details

Citation

Furstenberger C, Vuorinen A, Da Cunha T, Kratschmar DV, Saugy M, Schuster D, Odermatt A

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

Toxicol Sci. 2012 Apr;126(2):353-61. doi: 10.1093/toxsci/kfs022. Epub 2012 Jan 23.

PubMed ID
22273746 [ View in PubMed
]
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 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2)-dependent inactivation of glucocorticoids. Using recombinant human 11beta-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 11beta-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 11beta-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11beta-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11beta-HSD2. Structural modeling revealed similar binding modes for fluoxymesterone and cortisol, supporting a competitive mode of inhibition of 11beta-HSD2-dependent cortisol oxidation by this AAS. No direct modulation of mineralocorticoid receptor (MR) function was observed. Thus, 11beta-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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
FluoxymesteroneCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Inhibitor
Details
FormeboloneCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Inhibitor
Details
Hydrocortisone aceponateCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone acetateCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone butyrateCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone cypionateCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone phosphateCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone probutateCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone valerateCorticosteroid 11-beta-dehydrogenase isozyme 2ProteinHumans
Unknown
Not AvailableDetails