RT Journal Article
SR Electronic
T1 Changes in Mouse Liver Protein Glutathionylation after Acetaminophen Exposure
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 360
OP 368
DO 10.1124/jpet.111.187948
VO 340
IS 2
A1 Yang, Xi
A1 Greenhaw, James
A1 Ali, Akhtar
A1 Shi, Qiang
A1 Roberts, Dean W.
A1 Hinson, Jack A.
A1 Muskhelishvili, Levan
A1 Beger, Richard
A1 Pence, Lisa M.
A1 Ando, Yosuke
A1 Sun, Jinchun
A1 Davis, Kelly
A1 Salminen, William F.
YR 2012
UL http://jpet.aspetjournals.org/content/340/2/360.abstract
AB 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.