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Research ArticleToxicology

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

Evelin Krajnc, Michele Visentin, Zhibo Gai, Bruno Stieger, Sophia L. Samodelov, Stephanie Häusler and Gerd A. Kullak-Ublick
Journal of Pharmacology and Experimental Therapeutics November 2020, 375 (2) 239-246; DOI: https://doi.org/10.1124/jpet.120.000120
Evelin Krajnc
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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Michele Visentin
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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Zhibo Gai
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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Bruno Stieger
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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Sophia L. Samodelov
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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Stephanie Häusler
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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Gerd A. Kullak-Ublick
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (E.K., M.V., Z.G., B.S., S.L.S., S.H., G.A.K.-U.); Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland (E.K.);and Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland (G.A.K.-U.)
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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 2-hour exposure to a 50 μM 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. Nefazodone-induced ATP depletion in primary cultured mouse hepatocytes, mainly dependent on oxidative phosphorylation, was monophasic. 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.

SIGNIFICANCE STATEMENT Mitochondrial damage is a hallmark of drug-induced liver injury, yet other collateral alterations might contribute to the severity and evolution of the injury. Our in vitro study supports previous results arguing that a deficit in hepatic glucose metabolism, concomitant to the mitochondrial injury, might be cardinal in the prognosis of the initial insult to the liver. From a drug development standpoint, coupling anaerobic glycolysis and mitochondrial function assessment might increase the drug-induced liver injury preclinical screening performance.

Footnotes

    • Received May 21, 2020.
    • Accepted August 10, 2020.
  • This work was supported by the Swiss National Science Foundation [Grant 310030_175639 to G.A.K.-U.].

  • This work is part of the following published dissertation: Krajnc E (2020) Pathomechanisms of Drug-Induced Liver Injury: (i) An In Vitro Model of Nefazodone-Induced Cytotoxicity, and (ii) An In Vivo Model of Valproic Acid-Induced Hepatic Steatosis and Effects of Treatment with an FXR Ligand. Ph.D. thesis, ETH Zurich, Zurich, Switzerland.

  • https://doi.org/10.1124/jpet.120.000120.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 2
1 Nov 2020
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Research ArticleToxicology

Nefazodone Inhibits Anaerobic Glycolysis

Evelin Krajnc, Michele Visentin, Zhibo Gai, Bruno Stieger, Sophia L. Samodelov, Stephanie Häusler and Gerd A. Kullak-Ublick
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 239-246; DOI: https://doi.org/10.1124/jpet.120.000120

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Research ArticleToxicology

Nefazodone Inhibits Anaerobic Glycolysis

Evelin Krajnc, Michele Visentin, Zhibo Gai, Bruno Stieger, Sophia L. Samodelov, Stephanie Häusler and Gerd A. Kullak-Ublick
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 239-246; DOI: https://doi.org/10.1124/jpet.120.000120
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