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Untargeted Metabolomics Reveals Anaerobic Glycolysis as a Novel Target of the Hepatotoxic Antidepressant Nefazodone


Krajnc, Evelin; Visentin, Michele; Gai, Zhibo; Stieger, Bruno; Samodelov, Sophia L; Häusler, Stephanie; Kullak-Ublick, Gerd A (2020). Untargeted Metabolomics Reveals Anaerobic Glycolysis as a Novel Target of the Hepatotoxic Antidepressant Nefazodone. Journal of Pharmacology and Experimental Therapeutics, 375(2):239-246.

Abstract

Mitochondrial damage is considered a hallmark of drug-induced liver injury (DILI). However, despite the common molecular etiology, the evolution of the injury is usually unpredictable, with some cases that are mild and reversible upon discontinuation of the treatment and others characterized by irreversible acute liver failure. This suggests that additional mechanisms of damage play a role in determining the progression of the initial insult. To uncover novel pathways potentially involved in DILI, we investigated in vitro the metabolic perturbations associated with nefazodone, an antidepressant associated with acute liver failure. Several pathways associated with ATP production, including gluconeogenesis, anaerobic glycolysis and oxidative phosphorylation, were altered in human hepatocellular carcinoma-derived (Huh7) cells after two hour-exposure to a 50 microM extracellular concentration of nefazodone. In the presence or absence of glucose, ATP production of Huh7 cells was glycolysis- and oxidative phosphorylation-dependent, respectively. In glucose-containing medium, nefazodone-induced ATP depletion from Huh7 cells was biphasic. Huh7 cells in glucose-free medium were more sensitive to nefazodone than those in glucose-containing medium, losing the biphasic inhibition. Primary cultured mouse hepatocytes, mainly dependent on oxidative phosphorylation, were more sensitive than Huh7 cells to nefazodone exposure in glucose containing medium. At lower extracellular concentrations, nefazodone inhibited the oxygen consumption of Huh7 cells, whereas, at higher extracellular concentrations, it also inhibited the extracellular acidification. ATP content was rescued by increasing the extracellular concentration of glucose. In conclusion, nefazodone has a dual inhibitory effect on mitochondrial-dependent and mitochondrial-independent ATP production.

Abstract

Mitochondrial damage is considered a hallmark of drug-induced liver injury (DILI). However, despite the common molecular etiology, the evolution of the injury is usually unpredictable, with some cases that are mild and reversible upon discontinuation of the treatment and others characterized by irreversible acute liver failure. This suggests that additional mechanisms of damage play a role in determining the progression of the initial insult. To uncover novel pathways potentially involved in DILI, we investigated in vitro the metabolic perturbations associated with nefazodone, an antidepressant associated with acute liver failure. Several pathways associated with ATP production, including gluconeogenesis, anaerobic glycolysis and oxidative phosphorylation, were altered in human hepatocellular carcinoma-derived (Huh7) cells after two hour-exposure to a 50 microM extracellular concentration of nefazodone. In the presence or absence of glucose, ATP production of Huh7 cells was glycolysis- and oxidative phosphorylation-dependent, respectively. In glucose-containing medium, nefazodone-induced ATP depletion from Huh7 cells was biphasic. Huh7 cells in glucose-free medium were more sensitive to nefazodone than those in glucose-containing medium, losing the biphasic inhibition. Primary cultured mouse hepatocytes, mainly dependent on oxidative phosphorylation, were more sensitive than Huh7 cells to nefazodone exposure in glucose containing medium. At lower extracellular concentrations, nefazodone inhibited the oxygen consumption of Huh7 cells, whereas, at higher extracellular concentrations, it also inhibited the extracellular acidification. ATP content was rescued by increasing the extracellular concentration of glucose. In conclusion, nefazodone has a dual inhibitory effect on mitochondrial-dependent and mitochondrial-independent ATP production.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Medicine
Life Sciences > Pharmacology
Uncontrolled Keywords:Molecular Medicine, Pharmacology
Language:English
Date:1 November 2020
Deposited On:12 Feb 2021 15:39
Last Modified:13 Feb 2021 21:00
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1124/jpet.120.000120
PubMed ID:32848075
Project Information:
  • : FunderSNSF
  • : Grant ID310030_175639
  • : Project TitleRole of drug transporters and nuclear receptors in drug-induced liver and kidney injury

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