PT  - JOURNAL ARTICLE
AU  - Xi Yang
AU  - James Greenhaw
AU  - Akhtar Ali
AU  - Qiang Shi
AU  - Dean W. Roberts
AU  - Jack A. Hinson
AU  - Levan Muskhelishvili
AU  - Richard Beger
AU  - Lisa M. Pence
AU  - Yosuke Ando
AU  - Jinchun Sun
AU  - Kelly Davis
AU  - William F. Salminen
TI  - Changes in Mouse Liver Protein Glutathionylation after Acetaminophen Exposure
AID  - 10.1124/jpet.111.187948
DP  - 2012 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 360--368
VI  - 340
IP  - 2
4099  - http://jpet.aspetjournals.org/content/340/2/360.short
4100  - http://jpet.aspetjournals.org/content/340/2/360.full
SO  - J Pharmacol Exp Ther2012 Feb 01; 340
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.