The Anabolic Androgenic Steroid Fluoxymesterone Inhibits 11 -Hydroxysteroid Dehydrogenase 2-Dependent Glucocorticoid Inactivation

Recently, evidence was presented that uninephrectomy induces salt-sensitive hypertension in rats. The increase in blood pressure was abrogated by a mineralocorticoid receptor antagonist but not by an aldosterone synthase inhibitor. Here, we hypothesize that mineralocorticoid receptor activation occurred by an 11beta-hydroxy-glucocorticosteroid, as a consequence of dysregulated 11beta-hydroxysteroid dehydrogenase enzymes. Therefore, 3-week-old Sprague-Dawley rats were either uninephrectomized or sham operated and given a normal (0.4%) or high (8%)-salt diet. At week 8, a telemetric device was implanted, and during week 13 blood pressure continuously measured and urine was collected. The animals were sacrificed thereafter and liver and kidney were harvested. Steroid metabolites were analyzed by GC-MS and mRNA assessed by PCR. Uninephrectomy caused a distinct salt-sensitive hypertension. The increase in blood pressure correlated significantly with a decline in the apparent activity of 11beta-hydroxysteroid dehydrogenase 2 and an increase of 11beta-hydroxysteroid dehydrogenase 1, when urinary corticosterone metabolites were considered. These results were mirrored by the corresponding metabolite ratios assessed in renal and liver tissue. Changes in enzyme activities were in part explained by changes in the mRNA content. In conclusion, mineralocorticoid receptor-dependent salt sensitivity after UNX in rats appears to be mediated by glucocorticoids.

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“…; Fürstenberger et al. ) 11βHSD1 leads to hypertension (Masuzaki et al. ) and to a metabolic syndrome (Masuzaki et al.…”

Section: Discussionmentioning

confidence: 99%

Evidence for glucocorticoid-mediated hypertension after uninephrectomy

et al. 2013

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“…11β-HSD2 activity measurement in intact SW-620 and MCF-7 cells was determined as described earlier [43]. Briefly, 100 000 SW-620 and 50 000 MCF-7 cells per well were seeded in 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole

Beck

Bächler

Vuorinen

et al. 2017

Biochemical Pharmacology

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Impaired 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)-dependent cortisol inactivation can lead to electrolyte dysbalance, hypertension and cardiometabolic disease. Furthermore, placental 11β-HSD2 essentially protects the fetus from high maternal glucocorticoid levels, and its impaired function has been associated with altered fetal growth and a higher risk for cardio-metabolic diseases in later life. Despite its important role, 11β-HSD2 is not included in current off-target screening approaches. To identify potential 11β-HSD inhibitors among approved drugs, a pharmacophore model was used for virtual screening, followed by biological assessment of selected hits. This led to the identification of several azole fungicides as 11β-HSD inhibitors, showing a significant structure-activity relationship between azole scaffold size, 11β-HSD enzyme selectivity and inhibitory potency. A hydrophobic linker connecting the azole ring to the other, more polar end of the molecule was observed to be favorable for 11β-HSD2 inhibition and selectivity over 11β-HSD1. The most potent 11β-HSD2 inhibition, using cell lysates expressing recombinant human 11β-HSD2, was obtained for itraconazole (IC 139±14nM), its active metabolite hydroxyitraconazole (IC 223±31nM) and posaconazole (IC 460±98nM). Interestingly, experiments with mouse and rat kidney homogenates showed considerably lower inhibitory activity of these compounds towards 11β-HSD2, indicating important species-specific differences. Thus, 11β-HSD2 inhibition by these compounds is likely to be overlooked in preclinical rodent studies. Inhibition of placental 11β-HSD2 by these compounds, in addition to the known inhibition of cytochrome P450 enzymes and P-glycoprotein efflux transport, might contribute to elevated local cortisol levels, thereby affecting fetal programming.

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“…In this study, the androgen fluoxymesterone has shown to inhibit 11β-hydroxysteroid dehydrogenase, which may lead to decreased glucocorticoid inactivation and therefore to cortisol-induced mineralcorticoid receptor activation ending up in electrolyte disturbances. This could cause possible hypertension [ 67 ]. A recent study in recreational sports was conducted in 17 men given either the prohormone 3β-hydroxy-5α-androst-1-en-17-one or placebo where the treated group showed negative effects on cardiovascular and liver parameters [ 68 ].…”

Section: Adverse Effectsmentioning

confidence: 99%

Synthetic Androgens as Designer Supplements

Joseph

Parr

2015

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Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed.

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The Anabolic Androgenic Steroid Fluoxymesterone Inhibits 11 -Hydroxysteroid Dehydrogenase 2-Dependent Glucocorticoid Inactivation

Cited by 20 publications

References 44 publications

Evidence for glucocorticoid-mediated hypertension after uninephrectomy

Evidence for glucocorticoid-mediated hypertension after uninephrectomy

Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole

Synthetic Androgens as Designer Supplements

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