Mechanisms Of Drug-induced Toxicities

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ANNUAL REPORT FOR 2008 1. This year we discovered a pathway by which IL-4 induces the synthesis of gamma-glutamylcysteinyl ligase, the rate determining step in the synthesis of the cytoprotective molecule glutathione, and protects against AILI. Our findings suggest that IL-4 signaling causes the activation of the transcription factor AP-1, which in turn induces the gene expression of gamma-glutamylcysteinyl ligase. 2. This year we discovered a potential mechanism by which endogenous corticosterone released into the blood as a result of hepatocellular injury enhances the severity of AILI. Our findings suggest that corticosterone potentiates AILI at least in part by activating MAPK signaling. 3. This year we provide evidence suggesting that halothane-induced liver injury is caused at least in part, by enhancing ER stress and an unfolded protein response as a consequence of its reactive metabolite, trifluoroacetyl chloride, covalently modifying chaperone proteins in the ER.