Mechanisms of hepatotoxicity

Hartmut Jaeschke, Gregory James Gores, Arthur I. Cederbaum, Jack A. Hinson, Dominique Pessayre, John J. Lemasters

Research output: Contribution to journalArticle

940 Citations (Scopus)

Abstract

This review addresses recent advances in specific mechanisms of hepatotoxicity. Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress. In cholestatic disease, endogenously generated bile acids produce hepatocellular apoptosis by stimulating Fas translocation from the cytoplasm to the plasma membrane where self-aggregation occurs to trigger apoptosis. Kupffer cell activation and neutrophil infiltration extend toxic injury. Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation. The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1. CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress. In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury. In inducible nitric oxide synthase (iNOS) knockout mice, nitration is prevented, but unscavenged superoxide production then causes toxic lipid peroxidation to occur instead. Microvesicular steatosis, nonalcoholic steatohepatitis (NASH), and cytolytic hepatitis involve mitochondrial dysfunction, including impairment of mitochondrial fatty acid β-oxidation, inhibition of mitochondrial respiration, and damage to mitochondrial DNA. Induction of the mitochondrial permeability transition (MPT) is another mechanism causing mitochondrial failure, which can lead to necrosis from ATP depletion or caspase-dependent apoptosis if ATP depletion does not occur fully. Because of such diverse mechanisms, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use.

Original languageEnglish (US)
Pages (from-to)166-176
Number of pages11
JournalToxicological Sciences
Volume65
Issue number2
DOIs
StatePublished - 2002

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Nitration
Cytochrome P-450 CYP2E1
Oxidative stress
Kupffer Cells
Poisons
Apoptosis
Superoxides
Liver
Toxicity
Reactive Oxygen Species
Oxidative Stress
Ethanol
Adenosine Triphosphate
Chemical activation
Pharmaceutical Preparations
Neutrophil Activation
Peroxynitrous Acid
Neutrophil Infiltration
Wounds and Injuries
Nitric Oxide Synthase Type II

Keywords

  • Bile acids
  • Cholestasis
  • Cytochrome P4502E1
  • Kupffer cells
  • Microvesicular steatosis
  • Mitochondrial permeability transition
  • Neutrophils
  • Nitric oxide
  • Oxidative stress
  • Peroxynitrite

ASJC Scopus subject areas

  • Toxicology

Cite this

Jaeschke, H., Gores, G. J., Cederbaum, A. I., Hinson, J. A., Pessayre, D., & Lemasters, J. J. (2002). Mechanisms of hepatotoxicity. Toxicological Sciences, 65(2), 166-176. https://doi.org/10.1093/toxsci/65.2.166

Mechanisms of hepatotoxicity. / Jaeschke, Hartmut; Gores, Gregory James; Cederbaum, Arthur I.; Hinson, Jack A.; Pessayre, Dominique; Lemasters, John J.

In: Toxicological Sciences, Vol. 65, No. 2, 2002, p. 166-176.

Research output: Contribution to journalArticle

Jaeschke, H, Gores, GJ, Cederbaum, AI, Hinson, JA, Pessayre, D & Lemasters, JJ 2002, 'Mechanisms of hepatotoxicity', Toxicological Sciences, vol. 65, no. 2, pp. 166-176. https://doi.org/10.1093/toxsci/65.2.166
Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicological Sciences. 2002;65(2):166-176. https://doi.org/10.1093/toxsci/65.2.166
Jaeschke, Hartmut ; Gores, Gregory James ; Cederbaum, Arthur I. ; Hinson, Jack A. ; Pessayre, Dominique ; Lemasters, John J. / Mechanisms of hepatotoxicity. In: Toxicological Sciences. 2002 ; Vol. 65, No. 2. pp. 166-176.
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