As discussed earlier, we reported last year that halothane metabolism led to an unfolded protein response and subsequent liver injury that appeared to be due in part to a loss of important antioxidant proteins as a result of protein catabolism in the absence of protein synthesis. This year we discovered that other important cellular proteins are also lost from the liver by a similar mechanism, including those involved in liver autophagy. Conclusion: The murine model of halothane-induced liver injury continues to reveal novel mechanisms of DILD. Our findings this year suggest that the unfolded protein response induced by halothane can lead to liver injury by inhibiting hepatocellular autophagy, which has been reported to be an active process in protecting hepatocytes from death caused by a variety of etiologies. It is quite possible that liver injury caused by other drugs might also be mediated by similar pathways involving autophagy inhibition.

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National Heart, Lung, and Blood Institute
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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