Central role of mitochondria in drug-induced liver injury

Drug Metab Rev. 2012 Feb;44(1):34-87. doi: 10.3109/03602532.2011.604086. Epub 2011 Sep 6.


A frequent mechanism for drug-induced liver injury (DILI) is the formation of reactive metabolites that trigger hepatitis through direct toxicity or immune reactions. Both events cause mitochondrial membrane disruption. Genetic or acquired factors predispose to metabolite-mediated hepatitis by increasing the formation of the reactive metabolite, decreasing its detoxification, or by the presence of critical human leukocyte antigen molecule(s). In other instances, the parent drug itself triggers mitochondrial membrane disruption or inhibits mitochondrial function through different mechanisms. Drugs can sequester coenzyme A or can inhibit mitochondrial β-oxidation enzymes, the transfer of electrons along the respiratory chain, or adenosine triphosphate (ATP) synthase. Drugs can also destroy mitochondrial DNA, inhibit its replication, decrease mitochondrial transcripts, or hamper mitochondrial protein synthesis. Quite often, a single drug has many different effects on mitochondrial function. A severe impairment of oxidative phosphorylation decreases hepatic ATP, leading to cell dysfunction or necrosis; it can also secondarily inhibit ß-oxidation, thus causing steatosis, and can also inhibit pyruvate catabolism, leading to lactic acidosis. A severe impairment of β-oxidation can cause a fatty liver; further, decreased gluconeogenesis and increased utilization of glucose to compensate for the inability to oxidize fatty acids, together with the mitochondrial toxicity of accumulated free fatty acids and lipid peroxidation products, may impair energy production, possibly leading to coma and death. Susceptibility to parent drug-mediated mitochondrial dysfunction can be increased by factors impairing the removal of the toxic parent compound or by the presence of other medical condition(s) impairing mitochondrial function. New drug molecules should be screened for possible mitochondrial effects.

Publication types

  • Review

MeSH terms

  • Cell Respiration / drug effects
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • DNA, Mitochondrial / biosynthesis
  • DNA, Mitochondrial / drug effects
  • Drug-Related Side Effects and Adverse Reactions
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Humans
  • Immune System / metabolism
  • Liver / metabolism*
  • Liver / pathology
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism*
  • Mitochondria, Liver / pathology
  • Mitochondria, Liver / ultrastructure
  • Mitochondrial Proteins / biosynthesis
  • Mitochondrial Proteins / drug effects
  • Oxidation-Reduction
  • Pharmaceutical Preparations / metabolism
  • Reactive Oxygen Species / metabolism


  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Pharmaceutical Preparations
  • Reactive Oxygen Species