Mechanisms of hepatotoxicity.
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 beta-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.
Jaeschke
Hartmut
H
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Gores
Gregory J
GJ
Cederbaum
Arthur I
AI
Hinson
Jack A
JA
Pessayre
Dominique
D
Lemasters
John J
JJ
D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D002779:Cholestasis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D015262:Xenobiotics / Q000633:toxicity
D015262:Xenobiotics