Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity

Pharmacol Ther. 1995;67(1):101-54. doi: 10.1016/0163-7258(95)00012-6.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Bile Acids and Salts / administration & dosage
  • Bile Acids and Salts / pharmacology
  • Bile Acids and Salts / therapeutic use
  • Chemical and Drug Induced Liver Injury*
  • DNA Replication / drug effects
  • DNA Replication / genetics
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Electron Transport
  • Ethanol / toxicity
  • Fat Necrosis / chemically induced
  • Fatty Liver / etiology
  • Female
  • Hormones / administration & dosage
  • Hormones / pharmacology
  • Hormones / therapeutic use
  • Humans
  • Liver Diseases / metabolism
  • Metabolism, Inborn Errors / etiology
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Pregnancy
  • Pregnancy Complications / etiology
  • Reye Syndrome / etiology

Substances

  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents
  • Bile Acids and Salts
  • DNA, Mitochondrial
  • Hormones
  • Ethanol