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Prediction of Liver Injury Induced by Chemicals in Human With a Multiparametric Assay on Isolated Mouse Liver Mitochondria
- Source :
- Toxicological Sciences, Toxicological Sciences, Oxford University Press (OUP), 2012, 129 (2), pp.332-345. ⟨10.1093/toxsci/KFS197⟩, Toxicological Sciences, 2012, 129 (2), pp.332-345. ⟨10.1093/toxsci/KFS197⟩
- Publication Year :
- 2012
- Publisher :
- Oxford University Press, 2012.
-
Abstract
- International audience; Drug-induced liver injury (DILI) in humans is difficult to predict using classical in vitro cytotoxicity screening and regulatory animal studies. This explains why numerous compounds are stopped during clinical trials or withdrawn from the market due to hepatotoxicity. Thus, it is important to improve early prediction of DILI in human. In the present study, we hypothesized that this goal could be achieved by investigating drug-induced mitochondrial dysfunction as this toxic effect is a major mechanism of DILI. To this end, we developed a high-throughput screening platform using isolated mouse liver mitochondria. Our broad spectrum multiparametric assay was designed to detect the global mitochondrial membrane permeabilization (swelling), inner membrane permeabilization (transmembrane potential), outer membrane permeabilization (cytochrome c release) and alteration of mitochondrial respiration driven by succinate or malate/glutamate. A pool of 124 chemicals (mainly drugs) was selected, including 87 with documented DILI and 37 without reported clinical hepatotoxicity. Our screening assay revealed an excellent sensitivity for clinical outcome of DILI (94 or 92% depending on cut-off) and a high positive predictive value (89 or 82%). A highly significant relationship between drug-induced mitochondrial toxicity and DILI occurrence in patients was calculated (P
- Subjects :
- Drug
hepatotoxicity
media_common.quotation_subject
chemicals
Mitochondria, Liver
010501 environmental sciences
Biology
Mitochondrion
Pharmacology
Toxicology
01 natural sciences
Article
drugs
03 medical and health sciences
Mice
medicine
Animals
Humans
030304 developmental biology
0105 earth and related environmental sciences
media_common
Liver injury
Membrane Potential, Mitochondrial
0303 health sciences
Mice, Inbred BALB C
Cytochrome c
screening
[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
prediction
medicine.disease
3. Good health
mitochondria
Mitochondrial toxicity
Mechanism of action
biology.protein
DILI
Animal studies
medicine.symptom
Chemical and Drug Induced Liver Injury
Bacterial outer membrane
Subjects
Details
- Language :
- English
- ISSN :
- 10960929, 10966080, and 10966099
- Volume :
- 129
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Toxicological Sciences
- Accession number :
- edsair.doi.dedup.....87291b135cfbafd28bcc34eb5cfac551