Untargeted liquid chromatography-mass spectrometry metabolomics to assess drug-induced cholestatic features in HepaRG® cells.
Toxicol Appl Pharmacol
; 379: 114666, 2019 09 15.
Article
en En
| MEDLINE
| ID: mdl-31323262
Cholestasis is a liver disease associated with retention of bile in the liver, which leads to local hepatic inflammation and severe liver damage. In order to investigate the mode of action of drug-induced cholestasis, in vitro models have shown to be able to recapitulate important elements of this disease. In this study, we applied untargeted metabolomics to investigate the metabolic perturbances in HepaRG® cells exposed for 24â¯h and 72â¯h to bosentan, a cholestatic reference toxicant. Intracellular profiles were extracted and analysed with liquid chromatography and accurate-mass spectrometry. Metabolites of interest were selected using partial least-squares discriminant analysis and random forest classifier models. The observed metabolic patterns associated with cholestasis in vitro were complex. Acute (24â¯h) exposure revealed metabolites related to apoptosis, such as ceramide and triglyceride accumulation, in combination with phosphatidylethanolamine, choline and carnitine depletion. Metabolomic alterations during exposure to lower dosages and a prolonged exposure (72â¯h) included carnitine upregulation and changes in the polyamine metabolism. These metabolites were linked to changes in phospholipid metabolism, mitochondrial pathways and energy homeostasis. The metabolic changes confirmed the mitotoxic effects of bosentan and revealed the potential involvement of phospholipid metabolism as part of the mode of action of drug-induced cholestasis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Colestasis
/
Hígado
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2019
Tipo del documento:
Article
Pais de publicación:
Estados Unidos