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Titolo:
Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: Role of mitochondrial oxidant stress
Autore:
Knight, TR; Kurtz, A; Bajt, ML; Hinson, JA; Jaeschke, H;
Indirizzi:
Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USAUniv Arkansas Med Sci Little Rock AR USA 72205 Little Rock, AR 72205 USA
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 2, volume: 62, anno: 2001,
pagine: 212 - 220
SICI:
1096-6080(200108)62:2<212:VAHPFD>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
NITROTYROSINE-PROTEIN ADDUCTS; INDUCED HEPATIC NECROSIS; INDUCED HEPATOTOXICITY; IN-VIVO; COVALENT BINDING; REACTIVE OXYGEN; GLUTATHIONE-PEROXIDASE; RAT-LIVER; MICE; RESPIRATION;
Keywords:
peroxynitrite; nitrotyrosine; acetaminophen; allopurinol; liver failure; mitochondria; oxidant stress;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Jaeschke, H Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, 4301 W Markham St,Mailslot 638, Little Rock, AR 72205 USA Univ Arkansas Med Sci 4301 W Markham St,Mailslot 638 Little Rock AR USA 72205
Citazione:
T.R. Knight et al., "Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: Role of mitochondrial oxidant stress", TOXICOL SCI, 62(2), 2001, pp. 212-220

Abstract

Peroxynitrite may be involved in acetaminophen-induced liver damage. However, it is unclear if peroxynitrite is generated in hepatocytes or in the vasculature. To address this question, we treated C3Heb/FeJ mice with 300 mg/kg acetaminophen and assessed nitrotyrosine protein adducts as indicator for peroxynitrite formation. Vascular nitrotyrosine staining was evident before liver injury between 0.5 and 2 h after acetaminophen treatment. However,liver injury developed parallel to hepatocellular nitrotyrosine staining between 2 and 6 h after acetaminophen. The mitochondrial content of glutathione disulfide, as indicator of reactive oxygen formation determined 6 h after acetaminophen, increased from 2.8 +/- 0.6% in controls to 23.5 +/- 5.1%. A high dose of allopurinol (100 mg/kg) strongly attenuated acetaminophen protein-adduct formation and prevented the mitochondrial oxidant stress and liver injury after acetaminophen. Lower doses of allopurinol, which are equally effective in inhibiting xanthine oxidase, were not protective and had no effect on nitrotyrosine staining and acetaminophen protein adduct formation. In vitro experiments showed that allopurinol is not a direct scavengerof peroxynitrite. We conclude that there is vascular peroxynitrite formation during the first 2 h after acetaminophen treatment. On the other hand, reactive metabolites of acetaminophen bind to intracellular proteins and cause mitochondrial dysfunction and superoxide formation. Mitochondrial superoxide reacts with nitric oxide to form peroxynitrite, which is responsible for intracellular protein nitration. The pathophysiological relevance of vascular peroxynitrite for hepatocellular peroxynitrite formation and liver injury remains to be established.

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Documento generato il 30/03/20 alle ore 10:16:47