Inderbinen Silvia G, Zogg Michael, Kley Manuel, Smieško Martin, Odermatt Alex
Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland.
Computational Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, Basel 4056, Switzerland.
Toxicol Appl Pharmacol. 2021 Feb 1;412:115387. doi: 10.1016/j.taap.2020.115387. Epub 2020 Dec 31.
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 (IC values in the nanomolar range), the rat enzyme was moderately inhibited (1.5- to 6-fold higher IC values compared to human), and mouse and zebrafish 11β-HSD2 were very weakly inhibited (IC 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.
11β-羟基类固醇脱氢酶2（11β-HSD2）将活性11β-羟基糖皮质激素转化为无活性的11-酮形式，从而防止糖皮质激素不适当激活盐皮质激素受体。遗传缺陷或抑制剂破坏11β-HSD2活性会导致表观盐皮质激素过多综合征（AME），其特征为低钾血症、高钠血症和高血压。最近，已确定唑类抗真菌药伊曲康唑和泊沙康唑可有效抑制人11β-HSD2，并且有几例病例研究描述了获得性AME患者。为了开始理解为什么在临床前研究期间遗漏了这种药物不良反应，评估了伊曲康唑、其主要代谢物羟基伊曲康唑（OHI）和泊沙康唑对人和三种常用实验动物的11β-HSD2的抑制潜力。虽然所有三种化合物均能有效抑制人11β-HSD2（IC值在纳摩尔范围内），但大鼠酶受到中度抑制（IC值比人高1.5至6倍），而小鼠和斑马鱼的11β-HSD2受到的抑制非常微弱（IC值高于7μM）。对人和小鼠11β-HSD2进行序列比对并应用新生成的同源模型，发现在C末端区域和底物结合口袋存在显著差异。将小鼠11β-HSD2的C末端进行交换，并将Leu170、Ile172残基替换为人酶相应的His170、Glu172残基，导致对伊曲康唑和泊沙康唑的敏感性增加，类似于人11β-HSD2。这些结果为所研究的唑类抗真菌药观察到的物种特异性11β-HSD2抑制提供了解释。所获得结构-活性关系信息应有助于未来对11β-HSD2抑制剂的评估，并有助于选择合适的动物模型进行疗效和安全性研究。
