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In Vitro Assessment of Mitochondrial Toxicity to Predict Drug-Induced Liver Injury

  • Mathieu Porceddu
  • Nelly Buron
  • Pierre Rustin
  • Bernard Fromenty
  • Annie Borgne-SanchezEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Mitochondrial liability of drugs and other xenobiotics is a major issue for patients because such toxicity can damage different tissues and organs such as liver, heart, and muscle. Drug-induced mitochondrial toxicity is also a major concern for pharmaceutical industries. Indeed, it is now acknowledged that such mechanism of toxicity can induce severe, and sometimes fatal, liver injury which can lead to the interruption of clinical trials, or drug withdrawal after marketing, such as in the case of troglitazone. Therefore, drug-induced mitochondrial dysfunction is increasingly sought after by pharmaceutical companies by using reliable in vitro assays in order to discard potential mitochondrion-toxic drugs during drug discovery stage. This chapter presents the in vitro methods used to identify potential mitochondrion-toxic drugs. To this end, different types of biological materials are used such as isolated mouse liver mitochondria and the human hepatic HepaRG® cell line, which expresses the main enzymes and transcription factors involved in drug metabolism. The in vitro method we discussed allows to investigate several key mitochondrial parameters such as oxygen consumption, transmembrane potential, respiratory chain complex activities, and mtDNA levels. These investigations are able to detect not only direct and acute mitochondrial alterations due to parent drugs but also indirect and chronic mitochondrial liability that can be induced by secondary metabolites. Hence, it could be used to detect potential drug-induced mitochondrial liability and to understand the involved mechanisms.

Key words

DILI Drug-induced liver injury Hepatocytes Hepatotoxicity Liver Mitochondria Mitochondrial toxicity Oxidative stress Respiratory chain Transmembrane potential 

Notes

Acknowledgments

This review was supported by a grant from the Agence Nationale de la Recherche (ANR-16-CE18-0010-03 MITOXDRUGS). We are very grateful to Biopredic International (Rennes, France) and especially Dr. Christophe Chesné for providing HepaRG cells for the characterization experiments and Sandrine Camus for recommendations on HepaRG cell culture.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Mathieu Porceddu
    • 1
    • 2
  • Nelly Buron
    • 1
    • 2
  • Pierre Rustin
    • 3
  • Bernard Fromenty
    • 4
  • Annie Borgne-Sanchez
    • 1
    • 2
    Email author
  1. 1.MITOLOGICS Research LabHôpital Robert DebréParisFrance
  2. 2.MITOLOGICS SASParc BiocitechRomainvilleFrance
  3. 3.INSERM, UMR1141-PROTECTHôpital Robert DebréParisFrance
  4. 4.INSERM, INRA, Univ Rennes 1, Univ Bretagne Loire, Nutrition, Metabolism and Cancer (NuMeCan)RennesFrance

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