Abstract
11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) converts active 11β-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids. Disruption of 11β-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypokalemia, hypernatremia and hypertension. Recently, the azole antifungals itraconazole and posaconazole were identified to potently inhibit human 11β-HSD2, and several case studies described patients with acquired AME. To begin to understand why this adverse drug effect was missed during preclinical investigations, the inhibitory potential of itraconazole, its main metabolite hydroxyitraconazole (OHI) and posaconazole against 11β-HSD2 from human and three commonly used experimental animals was assessed. Whilst human 11β-HSD2 was potently inhibited by all three compounds (IC50 values in the nanomolar range), the rat enzyme was moderately inhibited (1.5- to 6-fold higher IC50 values compared to human), and mouse and zebrafish 11β-HSD2 were very weakly inhibited (IC50 values above 7 μM). Sequence alignment and application of newly generated homology models for human and mouse 11β-HSD2 revealed significant differences in the C-terminal region and the substrate binding pocket. Exchange of the C-terminus and substitution of residues Leu170,Ile172 in mouse 11β-HSD2 by the corresponding residues His170,Glu172 of the human enzyme resulted in a gain of sensitivity to itraconazole and posaconazole, resembling human 11β-HSD2. The results provide an explanation for the observed species-specific 11β-HSD2 inhibition by the studied azole antifungals. The obtained structure-activity relationship information should facilitate future assessments of 11β-HSD2 inhibitors and aid choosing adequate animal models for efficacy and safety studies.
Highlights
11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) converts active 11β-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids
Recent clinical studies and case reports evidenced that the systemi cally used azole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism (reviewed in (Beck et al 2020b))
These adverse effects have only recently been recognized in patients, mainly in those reaching high serum drug levels, and they have remained unrecognized in preclinical investigations
Summary
11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) converts active 11β-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids. In mineralocorticoid target tissues such as kidney, colon, salivary and sweat glands, 11β-HSD2 has a gate-keeper function to regulate the ac cess of cortisol to mineralocorticoid receptors (MR), thereby allowing specificity of aldosterone to activate MR (Edwards et al 1988; Funder et al 1988; Odermatt and Kratschmar 2012) By this mechanism, 11βHSD2 has an important role in the regulation of the electrolyte balance. Acquired forms of AME can be caused by the excessive consumption of licorice, con taining the potent 11β-HSD inhibitor glycyrrhetinic acid (GA) (reviewed in (Ferrari 2010)), and, as more recently reported, by the systemically administered azole antifungals posaconazole and itraconazole The importance of zebrafish has gained considerable attraction due to the low cost and because experiments with larvae during the first 96 h are not considered as animal experiment (Planchart et al 2016; Wrighton et al 2019)
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