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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Beck Katharina R., Bächler Murielle, Vuorinen Anna, Wagner Sandra, Akram Muhammad, Griesser Ulrich, Temml Veronika, Klusonova Petra, Yamaguchi Hideaki, Schuster Daniela, Odermatt Alex,
Project Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation
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Original article (peer-reviewed)

Journal Biochemical Pharmacology
Volume (Issue) 130
Page(s) 93 - 103
Title of proceedings Biochemical Pharmacology
DOI 10.1016/j.bcp.2017.01.010


© 2017 Elsevier Inc. 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 50 139 ± 14 nM), its active metabolite hydroxyitraconazole (IC 50 223 ± 31 nM) and posaconazole (IC 50 460 ± 98 nM). 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.