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

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Drug-Induced Liver Toxicity

Part of the book series: Methods in Pharmacology and Toxicology ((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.

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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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Authors and Affiliations

  1. MITOLOGICS Research Lab, Hôpital Robert Debré, Paris, France

    Mathieu Porceddu, Nelly Buron & Annie Borgne-Sanchez

  2. MITOLOGICS SAS, Parc Biocitech, Romainville, France

    Mathieu Porceddu, Nelly Buron & Annie Borgne-Sanchez

  3. INSERM, UMR1141-PROTECT, Hôpital Robert Debré, Paris, France

    Pierre Rustin

  4. INSERM, INRA, Univ Rennes 1, Univ Bretagne Loire, Nutrition, Metabolism and Cancer (NuMeCan), Rennes, France

    Bernard Fromenty

Authors
  1. Mathieu Porceddu
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  2. Nelly Buron
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  3. Pierre Rustin
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  4. Bernard Fromenty
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  5. Annie Borgne-Sanchez
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Corresponding author

Correspondence to Annie Borgne-Sanchez .

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Editors and Affiliations

  1. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA

    Minjun Chen

  2. Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    Yvonne Will

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Porceddu, M., Buron, N., Rustin, P., Fromenty, B., Borgne-Sanchez, A. (2018). In Vitro Assessment of Mitochondrial Toxicity to Predict Drug-Induced Liver Injury. In: Chen, M., Will, Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-7677-5_14

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  • DOI: https://doi.org/10.1007/978-1-4939-7677-5_14

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-7676-8

  • Online ISBN: 978-1-4939-7677-5

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