Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity.
Severe and prolonged impairment of mitochondrial beta-oxidation leads to microvesicular steatosis, and, in severe forms, to liver failure, coma and death. Impairment of mitochondrial beta-oxidation may be either genetic or acquired, and different causes may add their effects to inhibit beta-oxidation severely and trigger the syndrome. Drugs and some endogenous compounds can sequester coenzyme A and/or inhibit mitochondrial beta-oxidation enzymes (aspirin, valproic acid, tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine and tianeptine); they may inhibit both mitochondrial beta-oxidation and oxidative phosphorylation (endogenous bile acids, amiodarone, perhexiline and diethylaminoethoxyhexestrol), or they may impair mitochondrial DNA transcription (interferon-alpha), or decrease mitochondrial DNA replication (dideoxynucleoside analogues), while other compounds (ethanol, female sex hormones) act through a combination of different mechanisms. Any investigational molecule should be screened for such effects.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport; D000431:Ethanol / Q000633:toxicity; D005218:Fat Necrosis / Q000139:chemically induced; D005234:Fatty Liver / Q000209:etiology; D005260:Female; D006728:Hormones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000209:etiology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology; D012202:Reye Syndrome / Q000209:etiology
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D001647:Bile Acids and Salts; D004272:DNA, Mitochondrial; D006728:Hormones; D000431:Ethanol