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

ABSTRACT: Impaired 11?-hydroxysteroid dehydrogenase type 2 (11?-HSD2)-dependent cortisol inactivation can lead to electrolyte dysbalance, hypertension and cardiometabolic disease. Furthermore, placental 11?-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, 11?-HSD2 is not included in current off-target screening approaches. To identify potential 11?-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 11?-HSD inhibitors, showing a significant structure-activity relationship between azole scaffold size, 11?-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 11?-HSD2 inhibition and selectivity over 11?-HSD1. The most potent 11?-HSD2 inhibition, using cell lysates expressing recombinant human 11?-HSD2, was obtained for itraconazole (IC50 139±14nM), its active metabolite hydroxyitraconazole (IC50 223±31nM) and posaconazole (IC50 460±98nM). Interestingly, experiments with mouse and rat kidney homogenates showed considerably lower inhibitory activity of these compounds towards 11?-HSD2, indicating important species-specific differences. Thus, 11?-HSD2 inhibition by these compounds is likely to be overlooked in preclinical rodent studies. Inhibition of placental 11?-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.

SUBMITTER: Beck KR 

PROVIDER: S-EPMC6828556 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature