Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

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 ind...

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Bibliographic Details
Published in:Journal of hepatology 2011-04, Vol.54 (4), p.773-794
Main Authors: Begriche, Karima, Massart, Julie, Robin, Marie-Anne, Borgne-Sanchez, Annie, Fromenty, Bernard
Format: Article
Language:English
Subjects:
Adiponectin
Adiponectin - metabolism
Adipose Tissue
Adipose Tissue - drug effects
Adipose Tissue - metabolism
Alcoholic Intoxication
Alcoholic Intoxication - complications
Animals
Biological and medical sciences
Carbohydrate Metabolism
Carbohydrate Metabolism - drug effects
Cell Death
Cell Death - drug effects
Chemical and Drug Induced Liver Injury - etiology
Chemical and Drug Induced Liver Injury - genetics
Chemical and Drug Induced Liver Injury - metabolism
Diabetes Mellitus, Type 2
Diabetes Mellitus, Type 2 - complications
Drug toxicity and drugs side effects treatment
Drug-Induced Liver Injury
Drugs
Energy Metabolism
Energy Metabolism - drug effects
Fatty Acids
Fatty Acids - metabolism
Fatty Liver
Fatty Liver - etiology
Fatty Liver - metabolism
Gastroenterology and Hepatology
Gastroenterology. Liver. Pancreas. Abdomen
Genetic Predisposition to Disease
Genome, Mitochondrial
Hepatitis C
Hepatitis C - complications
Hepatotoxicity
Human health and pathology
Humans
Hépatology and Gastroenterology
Insulin Resistance
Leptin
Leptin - metabolism
Life Sciences
Lipid Metabolism
Lipid Metabolism - drug effects
Lipids
Medical sciences
Metabolic diseases
Mitochondria
Mitochondria, Liver
Mitochondria, Liver - drug effects
Mitochondria, Liver - metabolism
Mitochondrial Membrane Transport Proteins
Mitochondrial Membrane Transport Proteins - drug effects
Models, Biological
Obesity
Obesity - complications
Oxidation-Reduction
Oxidative Phosphorylation
Oxidative Phosphorylation - drug effects
Oxidative stress
Pharmacology. Drug treatments
Reactive Oxygen Species
Reactive Oxygen Species - metabolism
Steatosis
Toxicity: digestive system
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Summary: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).
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2010.11.006