Mechanism of protection by metallothionein against acetaminophen hepatotoxicity
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160 (United States)
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 (United States)
- Department of Pathology, Brackenridge Hospital, Austin, TX 78701 (United States)
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the US. Metallothionein (MT) expression attenuates APAP-induced liver injury. However, the mechanism of this protection remains incompletely understood. To address this issue, C57BL/6 mice were treated with 100 mumol/kg ZnCl{sub 2} for 3 days to induce MT. Twenty-four hours after the last dose of zinc, the animals received 300 mg/kg APAP. Liver injury (plasma ALT activities, area of necrosis), DNA fragmentation, peroxynitrite formation (nitrotyrosine staining), MT expression, hepatic glutathione (GSH), and glutathione disulfide (GSSG) levels were determined after 6 h. APAP alone caused severe liver injury with oxidant stress (increased GSSG levels), peroxynitrite formation, and DNA fragmentation, all of which were attenuated by zinc-induced MT expression. In contrast, MT knockout mice were not protected by zinc. Hydrogen peroxide-induced cell injury in primary hepatocytes was dependent only on the intracellular GSH levels but not on MT expression. Thus, the protective effect of MT in vivo was not due to the direct scavenging of reactive oxygen species. Zinc treatment had no effect on the early GSH depletion kinetics after APAP administration, which is an indicator of the metabolic activation of APAP to its reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). However, MT was able to effectively trap NAPQI by covalent binding. We conclude that MT scavenges some of the excess NAPQI after GSH depletion and prevents covalent binding to cellular proteins, which is the trigger for the propagation of the cell injury mechanisms through mitochondrial dysfunction and nuclear DNA damage.
- OSTI ID:
- 21344839
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 242; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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ANIMAL CELLS
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BODY
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CHEMICAL BONDS
CHLORIDES
CHLORINE COMPOUNDS
DIGESTIVE SYSTEM
DIRECT REACTIONS
DISEASES
DISULFIDES
DNA
DNA DAMAGES
DOSES
DRUGS
ELEMENTS
GLANDS
GLUTATHIONE
HALIDES
HALOGEN COMPOUNDS
HYDROGEN COMPOUNDS
HYDROGEN PEROXIDE
IN VIVO
INJURIES
KINETICS
KNOCK-OUT REACTIONS
LIVER
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MICE
MITOCHONDRIA
NECROSIS
NUCLEAR REACTIONS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXIDIZERS
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PEPTIDES
PEROXIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RODENTS
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ZINC
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ZINC HALIDES