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

被引：48

作者：

Beck, Katharina R. ^{[1
,2
]}

Baechler, Murielle ^{[1
,2
]}

Vuorinen, Anna ^{[1
,2
]}

Wagner, Sandra ^{[3
,4
]}

Akram, Muhammad ^{[3
,4
]}

Griesser, Ulrich ^{[5
]}

Temml, Veronika ^{[3
,4
]}

Klusonova, Petra ^{[1
,2
]}

Yamaguchi, Hideaki ^{[6
]}

Schuster, Daniela ^{[3
,4
]}

Odermatt, Alex ^{[1
,2
]}

机构：

[1] Univ Basel, Swiss Ctr Appl Human Toxicol, Klingelbergstr 50, CH-4056 Basel, Switzerland

[2] Univ Basel, Div Mol & Syst Toxicol, Dept Pharmaceut Sci, Pharmazentrum, Klingelbergstr 50, CH-4056 Basel, Switzerland

[3] Univ Innsbruck, Inst Pharm Pharmaceut Chem, Innrain 80-82, A-6020 Innsbruck, Austria

[4] Univ Innsbruck, CMBI, Comp Aided Mol Design Grp, Innrain 80-82, A-6020 Innsbruck, Austria

[5] Univ Innsbruck, Inst Pharm Pharmaceut Technol, Innrain 80-82, A-6020 Innsbruck, Austria

[6] Meijo Univ, Dept Appl Biol Chem, Nagoya, Aichi 4688502, Japan

来源：

BIOCHEMICAL PHARMACOLOGY | 2017年 / 130卷

基金：

奥地利科学基金会; 瑞士国家科学基金会;

关键词：

11 beta-Hydroxysteroid dehydrogenase; Virtual screening; Reproductive toxicity; Itraconazole; Posaconazole; Glucocorticoid; BETA-HYDROXYSTEROID DEHYDROGENASE; APPARENT MINERALOCORTICOID EXCESS; INTRAUTERINE GROWTH RESTRICTION; ANTENATAL CORTICOSTEROIDS; GLUCOCORTICOID-RECEPTOR; LICORICE CONSUMPTION; PROSPECTIVE COHORT; HUMAN HYPERTENSION; ANTIFUNGAL AGENT; MULTIPLE COURSES;

D O I：

10.1016/j.bcp.2017.01.010

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Impaired 11 beta-hydroxysteroid dehydrogenase type 2 (11(beta-HSD2)-dependent cortisol inactivation can lead to electrolyte dysbalance, hypertension and cardiometabolic disease. Furthermore, placental 11 beta-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 beta-HSD2 is not included in current off-target screening approaches. To identify potential 11 beta-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 beta-HSD inhibitors, showing a significant structure-activity relationship between azole scaffold size, 11 beta-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 beta-HSD2 inhibition and selectivity over 11 beta-HSD1. The most potent 11 beta-HSD2 inhibition, using cell lysates expressing recombinant human 11 beta-HSD2, was obtained for itraconazole (IC50 139 +/- 14 nM), its active metabolite hydroxyitraconazole (IC50 223 +/- 31 nM) and posaconazole (IC50 460 +/- 98 nM). Interestingly, experiments with mouse and rat kidney homogenates showed considerably lower inhibitory activity of these compounds towards 11 beta-HSD2, indicating important species-specific differences. Thus, 11 beta-HSD2 inhibition by these compounds is likely to be overlooked in preclinical rodent studies. Inhibition of placental 11 beta-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. (C) 2017 Elsevier Inc. All rights reserved.

引用

页码：93 / 103

页数：11

共 92 条

[1]

[Anonymous], DRUG DISCOV TODAY

[2]

[Anonymous], SPOR DRUG SAF SHEET

[3] Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species [J].