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

Autor: Daniela Schuster, Hideaki Yamaguchi, Veronika Temml, Alex Odermatt, Katharina Beck, Anna Vuorinen, Ulrich J. Griesser, Petra Klusonova, Murielle Bächler, Muhammad Safwan Akram, Sandra Wagner
Rok vydání: 2017
Předmět:
Zdroj: Biochemical Pharmacology. 130:93-103
ISSN: 0006-2952
DOI: 10.1016/j.bcp.2017.01.010
Popis: 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 amongst 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 toward 11β-HSD2, indicating important species-specific differences. Thus, 11β-HSD2 inhibition by these compounds are 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.
Databáze: OpenAIRE
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