Journal
ARCHIVES OF TOXICOLOGY
Volume 89, Issue 10, Pages 1847-1860Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-014-1334-3
Keywords
Mitochondrial injury; Hepatotoxicity; High-content screening; Statins
Categories
Funding
- ALIVE Foundation
- Spanish Ministry of Health through Instituto de Salud Carlos III [IF08/3638, PI10/0923, PI13/0986]
- Sara Borrell Contract from Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness
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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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