Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver
| Autor: | Julie Massart, Bernard Fromenty, Annie Borgne-Sanchez, Karima Begriche, Marie-Anne Robin |
|---|---|
| Přispěvatelé: | Department of Metabolism and Aging, The Scripps Research Institute, 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 ), Mitologics SAS, Hôpital Robert Debré, The Scripps Research Institute [La Jolla, San Diego], 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 ), Brébion, Alice |
| Rok vydání: | 2011 |
| Předmět: |
Leptin
MESH: Oxidation-Reduction MESH: Cell Death Steatosis MESH: Carbohydrate Metabolism Microvesicular Steatosis Mitochondria Liver Mitochondrial Membrane Transport Proteins Oxidative Phosphorylation 0302 clinical medicine Nonalcoholic fatty liver disease MESH: Obesity MESH: Animals MESH: Fatty Liver MESH: Lipid Metabolism Liver injury 0303 health sciences Fatty Acids MESH: Energy Metabolism MESH: Genetic Predisposition to Disease Drugs MESH: Reactive Oxygen Species MESH: Mitochondrial Membrane Transport Proteins MESH: Adiponectin Hepatitis C Lipids Mitochondria MESH: Fatty Acids 3. Good health MESH: Insulin Resistance Mitochondrial respiratory chain Adipose Tissue 030220 oncology & carcinogenesis Carbohydrate Metabolism Adiponectin MESH: Genome Mitochondrial Chemical and Drug Induced Liver Injury MESH: Mitochondria Liver Oxidation-Reduction MESH: Adipose Tissue MESH: Diabetes Mellitus Type 2 Cell death MESH: Drug-Induced Liver Injury medicine.medical_specialty Biology Models Biological 03 medical and health sciences MESH: Oxidative Phosphorylation Internal medicine medicine Animals Humans Genetic Predisposition to Disease Obesity 030304 developmental biology MESH: Hepatitis C MESH: Humans Hepatology Mitochondrial Permeability Transition Pore Hepatotoxicity MESH: Models Biological [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Lipid metabolism MESH: Leptin Lipid Metabolism medicine.disease [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Fatty Liver Endocrinology Diabetes Mellitus Type 2 MESH: Alcoholic Intoxication Mitochondrial permeability transition pore Oxidative stress Genome Mitochondrial Insulin Resistance Steatohepatitis Energy Metabolism Reactive Oxygen Species Alcoholic Intoxication |
| Zdroj: | Journal of Hepatology Journal of Hepatology, Elsevier, 2011, 54 (4), pp.773-94. ⟨10.1016/j.jhep.2010.11.006⟩ Journal of Hepatology, 2011, 54 (4), pp.773-94. ⟨10.1016/j.jhep.2010.11.006⟩ |
| ISSN: | 0168-8278 1600-0641 |
| Popis: | International audience; Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis). |
| Databáze: | OpenAIRE |
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