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Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole.
Biochem Pharmacol 2017; 130:93-103BP

Abstract

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 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 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 (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 11β-HSD2, indicating important species-specific differences. Thus, 11β-HSD2 inhibition by these compounds is 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.

Authors+Show Affiliations

Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: katharina.beck@unibas.ch.Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: murielle.baechler@stud.unibas.ch.Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: anna.vuorinen1@gmail.com.Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: sandra.wagner@student.uibk.ac.at.Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: muhammad.akram@uibk.ac.at.Institute of Pharmacy/Pharmaceutical Technology, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: ulrich.griesser@uibk.ac.at.Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: veronika.temml@uibk.ac.at.Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: petra.klusonova@unibas.ch.Department of Applied Biological Chemistry, Meijo University, Nagoya 468-8502, Japan. Electronic address: hyamagu@meijo-u.ac.jp.Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: daniela.schuster@uibk.ac.at.Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28131847

Citation

Beck, Katharina R., et al. "Inhibition of 11β-hydroxysteroid Dehydrogenase 2 By the Fungicides Itraconazole and Posaconazole." Biochemical Pharmacology, vol. 130, 2017, pp. 93-103.
Beck KR, Bächler M, Vuorinen A, et al. Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. Biochem Pharmacol. 2017;130:93-103.
Beck, K. R., Bächler, M., Vuorinen, A., Wagner, S., Akram, M., Griesser, U., ... Odermatt, A. (2017). Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. Biochemical Pharmacology, 130, pp. 93-103. doi:10.1016/j.bcp.2017.01.010.
Beck KR, et al. Inhibition of 11β-hydroxysteroid Dehydrogenase 2 By the Fungicides Itraconazole and Posaconazole. Biochem Pharmacol. 2017 04 15;130:93-103. PubMed PMID: 28131847.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. AU - Beck,Katharina R, AU - Bächler,Murielle, AU - Vuorinen,Anna, AU - Wagner,Sandra, AU - Akram,Muhammad, AU - Griesser,Ulrich, AU - Temml,Veronika, AU - Klusonova,Petra, AU - Yamaguchi,Hideaki, AU - Schuster,Daniela, AU - Odermatt,Alex, Y1 - 2017/01/25/ PY - 2016/12/23/received PY - 2017/01/23/accepted PY - 2017/1/31/pubmed PY - 2017/5/10/medline PY - 2017/1/30/entrez KW - 11β-Hydroxysteroid dehydrogenase KW - Albendazole (PubChem CID: 2082) KW - Butoconazole (PubChem CID: 47472) KW - Climbazole (PubChem CID: 37907) KW - Glucocorticoid KW - Hydroxyitraconazole (PubChem CID: 108222) KW - Itraconazole KW - Itraconazole (PubChem CID: 55283) KW - Ketoconazole (PubChem CID: 47576) KW - Posaconazole KW - Posaconazole (PubChem CID: 468595) KW - Reproductive toxicity KW - Sertaconazole (PubChem CID: 65863) KW - Terconazole (PubChem CID: 441383) KW - Tioconazole (PubChem CID: 5482) KW - Virtual screening SP - 93 EP - 103 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 130 N2 - 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 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 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 (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 11β-HSD2, indicating important species-specific differences. Thus, 11β-HSD2 inhibition by these compounds is 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/28131847/Inhibition_of_11β-hydroxysteroid_dehydrogenase_2_by_the_fungicides_itraconazole_and_posaconazole L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(17)30040-0 DB - PRIME DP - Unbound Medicine ER -