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TOXICOLOGY

Scavenging Peroxynitrite with Glutathione Promotes Regeneration and Enhances Survival during Acetaminophen-Induced Liver Injury in Mice

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (M.L.B., T.R.K., H.J.); Liver Research Institute, University of Arizona College of Medicine, Tucson, Arizona (M.L.B., T.R.K., H.J.); and Department of Pathology, University of Texas Health Science Center, Houston, Texas (A.F.)

Acetaminophen (AAP) overdose causes formation of peroxynitrite in centrilobular hepatocytes. Treatment with glutathione (GSH) after AAP accelerated recovery of mitochondrial GSH levels, which scavenged peroxynitrite and protected against liver injury at 6 h. The objective of this investigation was to evaluate whether GSH treatment has a long-term protective effect against AAP-induced injury and whether it promotes liver regeneration. AAP (300 mg/kg) induced severe centrilobular necrosis and increased plasma alanine aminotransferase (ALT) activities (24 h: 3680 ± 320 U/liter) in fasted C3Heb/FeJ mice. Only 53% of the animals survived for 24 h. Hepatic glutathione levels were still suppressed by 62% at 24 h compared with untreated controls (19.7 ± 2.6 µmol/g). Glutathione disulfide (GSSG) concentrations were elevated by 455% compared with controls (74 ± 3 nmol/g liver). Treatment with GSH at 1.5 h after AAP treatment attenuated liver necrosis and plasma ALT activities by 62 to 66% at 24 h. All animals survived up to 7 days. The hepatic GSH content recovered to control values; however, the GSSG levels were still elevated at 48 h (252 ± 26 nmol/g). Expression of proliferating cell nuclear antigen (PCNA) and cell cycle proteins cyclin D₁ and p21 were not detectable in controls or after AAP alone. Treatment with GSH after AAP induced expression of cyclin D₁, p21, and PCNA (12–48 h). Thus, GSH treatment after AAP provided long-term hepatoprotection and promotes progression of cell cycle activation in hepatocytes.

Address correspondence to: Dr. Mary Lynn Bajt, Liver Research Institute, University of Arizona, College of Medicine, 1501 N. Campbell Avenue, Room 6309, Tucson, AZ 85724. E-mail: mlb3{at}email.arizona.edu

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