Species-specific differences in the inhibition of 11β-hydroxysteroid dehydrogenase 2 by itraconazole and posaconazole.
11-beta-Hydroxysteroid Dehydrogenase Type 2
/ antagonists & inhibitors
Antifungal Agents
/ toxicity
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ toxicity
HEK293 Cells
Humans
Itraconazole
/ toxicity
Mineralocorticoid Excess Syndrome, Apparent
/ chemically induced
Protein Conformation
Species Specificity
Structure-Activity Relationship
Triazoles
/ toxicity
Zebrafish Proteins
/ antagonists & inhibitors
11beta-Hydroxysteroid Dehydrogenase
Azole Fungicide
Glucocorticoid
Hypertension
Pseudohyperaldosteronism
Species Difference
Journal
Toxicology and applied pharmacology
ISSN: 1096-0333
Titre abrégé: Toxicol Appl Pharmacol
Pays: United States
ID NLM: 0416575
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
received:
22
10
2020
revised:
11
12
2020
accepted:
23
12
2020
pubmed:
3
1
2021
medline:
12
5
2021
entrez:
2
1
2021
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 33387577
pii: S0041-008X(20)30509-3
doi: 10.1016/j.taap.2020.115387
pii:
doi:
Substances chimiques
Antifungal Agents
0
Enzyme Inhibitors
0
Triazoles
0
Zebrafish Proteins
0
Itraconazole
304NUG5GF4
posaconazole
6TK1G07BHZ
11-beta-Hydroxysteroid Dehydrogenase Type 2
EC 1.1.1.146
HSD11B2 protein, human
EC 1.1.1.146
HSD11B2 protein, mouse
EC 1.1.1.146
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
115387Informations de copyright
Copyright © 2020. Published by Elsevier Inc.