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Vol. 303, Issue 2, 468-475, November 2002
Department of Pharmacology and Toxicology, University of Arkansas
for Medical Sciences, Little Rock, Arkansas (T.R.K., H.J.); Institute
of Environmental Health Sciences, Wayne State University, Detroit,
Michigan (Y.-S.H.); and Department of Pathology, University of Texas
Health Science Center, Houston, Texas (A.F.).
Acetaminophen (AAP) overdose causes formation of nitrotyrosine, a
footprint of peroxynitrite, in centrilobular hepatocytes. The
importance of peroxynitrite for the pathophysiology, however, is
unclear. C3Heb/FeJ mice were treated with 300 mg/kg AAP. To accelerate
the restoration of hepatic glutathione (GSH) levels as potential
endogenous scavengers of peroxynitrite, some groups of animals received
200 mg of GSH/kg i.v. at different time points after AAP. AAP induced
severe liver cell damage at 6 h. Total liver and mitochondrial
glutathione levels decreased by >90% at 1 h but recovered to 75 and 45%, respectively, of untreated values at 6 h after AAP. In
addition, the hepatic and mitochondrial glutathione disulfide (GSSG)
content was significantly increased over baseline, suggesting a
mitochondrial oxidant stress. Moreover, centrilobular hepatocytes
stained for nitrotyrosine. Treatment with GSH at t = 0 restored hepatic GSH levels and completely prevented the
mitochondrial oxidant stress, peroxynitrite formation, and liver cell
injury. In contrast, treatment at 1.5 and 2.25 h restored hepatic
and mitochondrial GSH levels but did not prevent the increase in GSSG formation. Nitrotyrosine adduct formation and liver injury, however, was substantially reduced. GSH treatment at 3 h after AAP was ineffective. Similar results were obtained when these experiments were
repeated with glutathione peroxidase-deficient animals. Our data
suggest that early GSH treatment (t = 0) prevented
cell injury by improving the detoxification of the reactive metabolite
of AAP. Delayed GSH treatment enhanced hepatic GSH levels, which scavenged peroxynitrite in a spontaneous reaction. Thus, peroxynitrite is an important mediator of AAP-induced liver cell necrosis.
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