Mechanisms Of Drug-induced Toxicities

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

ANNUAL REPORT FOR 2008[unreadable] [unreadable] 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.[unreadable] [unreadable] 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.[unreadable] [unreadable] 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.