1. Mitochondrial involvement in drug-induced liver injury
- Author
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Pessayre, Dominique, Mansouri, Abdellah, Berson, Alain, Fromenty, Bernard, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
- Subjects
MESH: Drug-Induced Liver Injury ,Steatosis ,Mitochondrial Diseases ,Drug-induced liver injury ,Drug-Related Side Effects and Adverse Reactions ,Apoptosis ,Mitochondria, Liver ,Mitochondrial Membrane Transport Proteins ,Hepatitis ,MESH: Drug Therapy ,Necrosis ,MESH: Mitochondrial Membranes ,Animals ,Humans ,MESH: Animals ,Biotransformation ,MESH: Necrosis ,MESH: Biotransformation ,MESH: DNA Damage ,MESH: Oxidative Stress ,MESH: Humans ,Mitochondrial Permeability Transition Pore ,MESH: Apoptosis ,Hepatotoxicity ,MESH: Energy Metabolism ,food and beverages ,MESH: Mitochondrial Membrane Transport Proteins ,MESH: Mitochondrial Diseases ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Mitochondria ,Oxidative Stress ,Mitochondrial Membranes ,Chemical and Drug Induced Liver Injury ,MESH: Mitochondria, Liver ,Energy Metabolism ,DNA Damage - Abstract
International audience; Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies.
- Published
- 2009