Immunoblot analysis of liver homogenates at 6 and 12 hours after halothane treatment showed that female Balb/cJ mice had higher levels of trifluoroacetylated (TFA)-protein adducts than those found in livers of female C57BL/6J mice. The Balb/cJ mice also had diminished levels of hepatic glutathione (GSH), gamma-glutamylcysteine-ligase, the rate determining step in GSH synthesis, and antioxidant proteins peroxiredoxin-1 and 5. These mice also had elevated hepatic levels of phospho-eukaryotic initiation factor 2 that can have a crucial role in inhibiting protein translation as a result of endoplasmic reticulum (ER)stress caused by an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. Conclusion: Approximately ten years ago we purified several TFA-protein adducts of halothane from livers of rats and identified them as chaperones involved in protein folding. We hypothesized that the posttranslational modification of these proteins by the trifluoroacetyl chloride metabolite of halothane might inhibit the chaperone activity and affect protein folding of newly synthesize proteins and hepatocyte viability. The results presented here support this hypothesis by showing that susceptibility of mice to halothane-induced liver injury correlates with the level of hepatic TFA-protein adducts and is associated with ER stress. The loss of antioxidant proteins following halothane treatment may be caused by protein turnover occurring concurrently with protein synthesis inhibition due to ER stress. Oxidative stress can contribute to halothane-induced liver injury by activating hepatocellular death pathways and inducing further ER stress by causing the formation of misfolded oxidized proteins. It is quite possible that factors regulating ER stress may play a role in determining susceptibility of patients to DILD.
| Masson, Mary Jane; Collins, Lindsay A; Carpenter, Leah D et al. (2010) Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice. Biochem Biophys Res Commun 397:453-8 |
