title: Changes in mouse liver protein glutathionylation after acetaminophen exposure.
abstract: The role of protein glutathionylation in acetaminophen (APAP)-induced liver injury was investigated in this study. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase and aspartate aminotransferase levels and liver necrosis in a dose-dependent manner. The ratio of GSH to GSSG was decreased in a dose-dependent manner, suggesting that APAP produced a more oxidizing environment within the liver. Despite the increased oxidation state, the level of global protein glutathionylation was decreased at 1 h and continued to decline through 24 h. Immunohistochemical localization of glutathionylated proteins showed a complex dynamic change in the lobule zonation of glutathionylated proteins. At 1 h after APAP exposure, the level of glutathionylation decreased in the single layer of hepatocytes around the central veins but increased mildly in the remaining centrilobular hepatocytes. This increase correlated with the immunohistochemical localization of APAP covalently bound to protein. Thereafter, the level of glutathionylation decreased dramatically over time in the centrilobular regions with major decreases observed at 6 and 24 h. Despite the overall decreased glutathionylation, a layer of cells lying between the undamaged periportal region and the damaged centrilobular hepatocytes exhibited high levels of glutathionylation at 3 and 6 h in all samples and in some 24-h samples that had milder injury. These temporal and zonal pattern changes in protein glutathionylation after APAP exposure indicate that protein glutathionylation may play a role in protein homeostasis during APAP-induced hepatocellular injury.
authors: Division of Systems Biology, Food and Drug Administration/National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors: Xi
authors: X
authors: Yang
authors: James
authors: J
authors: Greenhaw
authors: Akhtar
authors: A
authors: Ali
authors: Qiang
authors: Q
authors: Shi
authors: Dean W
authors: DW
authors: Roberts
authors: Jack A
authors: JA
authors: Hinson
authors: Levan
authors: L
authors: Muskhelishvili
authors: Richard
authors: R
authors: Beger
authors: Lisa M
authors: LM
authors: Pence
authors: Yosuke
authors: Y
authors: Ando
authors: Jinchun
authors: J
authors: Sun
authors: Kelly
authors: K
authors: Davis
authors: William F
authors: WF
authors: Salminen
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis / Q000097:blood / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism*
chemical_list: D011506:Proteins; D000082:Acetaminophen; C063450:3-(cystein-S-yl)paracetamol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D019803:Glutathione Disulfide