Cell Biology and Toxicology

, Volume 15, Issue 6, pp 367–373

Hepatotoxicity due to mitochondrial dysfunction

  • D. Pessayre
  • A. Mansouri
  • D. Haouzi
  • B. Fromenty
Article

Abstract

Mitochondria are involved in fatty acid β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, which provide most of the cell energy. Mitochondria are also the main source of reactive oxygen species in the cell and are involved in cell demise through opening of the mitochondrial permeability transition pore. It was therefore to be expected that mitochondrial dysfunction could be a major mechanism of drug-induced liver disease. Microvesicular steatosis (which may cause liver failure, coma, and death) is the consequence of severe impairment of mitochondrial β-oxidation. Endogenous compounds (such as cytokines or female sex hormones) or xenobiotics (including toxins such as ethanol and drugs such as aspirin, valproic acid, ibuprofen, or zidovudine) can inhibit β-oxidation directly or through a primary effect on the mitochondrial genome or the respiratory chain itself. In some patients, infections and cytokines, or inborn errors of β-oxidation enzymes or the mitochondrial genome, may favor the appearance of drug-induced microvesicular steatosis. Nonalcoholic steatohepatitis may develop under conditions causing prolonged, microvesicular, and/or macrovacuolar steatosis. In this condition, chronic impairment of mitochondrial β-oxidation (causing steatosis) and the respiratory chain (increasing the production of ROS) lead to lipid peroxidation, which, in turn, may cause the diverse lesions of steatohepatitis, namely, necrosis, inflammation, Mallory's bodies, and fibrosis. Finally, mitochondria are involved in several forms of drug-induced cytolytic hepatitis, through inhibition or uncoupling of respiration or through a drug-induced or reactive metabolite-induced mitochondrial permeability transition. The latter effect commits hepatocytes to either apoptosis or necrosis, depending on the number of organelles that have undergone the permeability transition.

apoptosis drugs hepatitis mitochondria steatosis steatohepatitis 

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Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • D. Pessayre
    • 1
  • A. Mansouri
    • 1
  • D. Haouzi
    • 1
  • B. Fromenty
    • 1
  1. 1.INSERM U481 and Centre de Recherche sur les Hépatites Virales de l'Association Claude BernardHôpital BeaujonClichyFrance

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