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Titolo:
Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity
Autore:
Michael, SL; Mayeux, PR; Bucci, TJ; Warbritton, AR; Irwin, LK; Pumford, NR; Hinson, JA;
Indirizzi:
Univ Arkansas Med Sci, Coll Med, Dept Pharmacol & Toxicol, Little Rock, AR72205 USA Univ Arkansas Med Sci Little Rock AR USA 72205 , Little Rock, AR72205 USA Pathol Associates Ins, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA Pathol Associates Ins Jefferson AR USA 72079 Res, Jefferson, AR 72079 USA
Titolo Testata:
NITRIC OXIDE-BIOLOGY AND CHEMISTRY
fascicolo: 5, volume: 5, anno: 2001,
pagine: 432 - 441
SICI:
1089-8603(200110)5:5<432:AHIMLI>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
NITROTYROSINE-PROTEIN ADDUCTS; PARA-BENZOQUINONE IMINE; LIPID-PEROXIDATION; COVALENT BINDING; IMMUNOHISTOCHEMICAL LOCALIZATION; CARBON-TETRACHLORIDE; TREATED MICE; PEROXYNITRITE; TOXICITY; HEPATOCYTES;
Keywords:
acetaminophen; peroxynitrite; nitrotyrosine; acetaminophen-cysteine; lipid peroxidation; liver necrosis; inducible nitric oxide synthase; hepatotoxicity.;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Hinson, JA Univ Arkansas Med Sci, Coll Med, Dept Pharmacol & Toxicol, Little Rock, AR72205 USA Univ Arkansas Med Sci Little Rock AR USA 72205 ck, AR72205 USA
Citazione:
S.L. Michael et al., "Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity", NITRIC OXID, 5(5), 2001, pp. 432-441

Abstract

We recently reported that nitrotyrosine and acetaminophen (APAP)-cysteine protein adducts colocalize in the hepatic centrilobular cells following a toxic dose of A-PAP to mice. Whereas APAP-adducts are formed by reaction of the metabolite N-acetyl-p-benzoquinone imine with cysteine, nitrotyrosine residues are formed by reaction of tyrosine with peroxynitrite. Peroxynitrite is formed from nitric oxide (NO) and superoxide. This manuscript examinesAPAP (300 mg/kg) hepatotoxicity in mice lacking inducible nitric oxide synthase activity (NOS2 null or knockout mice; C57BL/6-Nos2(tm1Lau)) and in the wildtype mice. In a time course the ALT levels in the exposed NOS2 null mice were approximately 50% of the wildtype mice; however, histological examination of liver sections indicated similar levels of centrilobular hepaticnecrosis in both wild-type and NOS2 null mice. Serum nitrate plus nitrite levels (NO synthesis) were identical in saline-treated NOS2 null and wild-type mice (53 +/- 2 muM). APAP increased NO synthesis in wild-type mice only. The increases paralleled the increases in ALT levels with peak levels of serum nitrate plus nitrite at 6 h (168 +/- 27 muM). In wild-type mice hepatic tyrosine nitration was greatly increased relative to saline treated controls. Tyrosine nitration increased in NOS2 null mice also, but the increasewas much less. APAP increased hepatic malonaldehyde levels (lipid peroxidation) in NOS2 null mice only. The results suggest the presence of multiple pathways to APAP-mediated hepatic necrosis, one via nitrotyrosine, as in the wild-type mice, and another that is not dependent upon inducible nitric oxide synthase activity, but which may involve increased superoxide. (C) 2001 Academic Press.

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Documento generato il 07/04/20 alle ore 22:44:02