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High-content screening of drug-induced mitochondrial impairment in hepatic cells: effects of statins

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Abstract

A frequent mechanism for drug-induced liver injury (DILI) is mitochondrial impairment, and early evaluation of new drugs for their potential to cause mitochondrial dysfunction is becoming an important task for drug development. To this end, we designed a high-content screening assay to study mitochondrial-induced hepatotoxicity in HepG2 cells in detail. Simultaneous assessment of mitochondrial mass and cell viability in cells exposed for 24 h to compounds provides preliminary information on the mitochondrial- or nonmitochondrial-related hepatotoxic potential of compounds. To fully address the mechanisms implicated in mitochondrial impairment, prelethal changes in mitochondrial superoxide production, mitochondrial membrane potential, mitochondrial permeability transition, intracellular calcium concentration and apoptotic cell death were studied in cells incubated for 1 h with compounds. The assay correctly classified a set of well-known mitochondrial toxicants and negative controls and revealed high sensitivity for the detection of mitochondrial DILI and the establishment of different mitochondrial toxicity risks (low to high). This procedure was used for analysing the potential mitochondrial impairment of six statins to determine their clinical risk. All the tested statins produced mitochondrial impairment, although they showed different levels of toxicity (low-medium toxicity risk). The results suggest that this cell-based assay is a promising in vitro approach to predict the potential of drug candidates to induce mitochondrial-associated hepatotoxicity.

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Abbreviations

CI:

Cumulative index

DILI:

Drug-induced liver injury

HCS:

High-content screening

MEC:

Minimal effective concentration

MMP:

Mitochondrial membrane potential

MPT:

Mitochondrial permeability transition

MTR:

Mitochondrial toxicity risk

PI:

Propidium iodide

TMRM:

Tetramethylrhodamine methyl ester

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Acknowledgments

The authors acknowledge financial support from the ALIVE Foundation and the Spanish Ministry of Health through IF08/3638, PI10/0923, and PI13/0986 (Instituto de Salud Carlos III). L.T. was a recipient of a Sara Borrell Contract from the Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Unidad de Hepatología Experimental, Torre A, Instituto Investigación Sanitaria La Fe (IIS La Fe), Bulevard Sur s/n, 46026, Valencia, Spain

    Laia Tolosa, Antonio Carmona, José V. Castell, M. José Gómez-Lechón & M. Teresa Donato

  2. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain

    José V. Castell & M. Teresa Donato

  3. CIBERehd, FIS, 08036, Barcelona, Spain

    José V. Castell, M. José Gómez-Lechón & M. Teresa Donato

Authors
  1. Laia Tolosa
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  2. Antonio Carmona
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  3. José V. Castell
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  4. M. José Gómez-Lechón
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  5. M. Teresa Donato
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Corresponding author

Correspondence to M. José Gómez-Lechón.

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M. José Gómez-Lechón and M. Teresa Donato shared supervision.

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Tolosa, L., Carmona, A., Castell, J.V. et al. High-content screening of drug-induced mitochondrial impairment in hepatic cells: effects of statins. Arch Toxicol 89, 1847–1860 (2015). https://doi.org/10.1007/s00204-014-1334-3

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