Mechanisms Of Drug-induced Toxicities

2008年年报 1.今年我们发现了一条途径，通过IL-4诱导合成γ-谷氨酰半胱氨基连接酶，这是细胞保护分子谷胱甘肽合成的决定步骤，并对ALI具有保护作用。我们的发现表明，IL-4信号导致转录因子AP-1的激活，进而诱导γ-谷氨酰半胱氨基连接酶的基因表达。 2.今年我们发现了一个潜在的机制，即肝细胞损伤导致内源性皮质酮释放到血液中，从而增加了AILI的严重程度。我们的发现表明，皮质酮至少部分地通过激活MAPK信号来增强AILI。 3.今年我们提供的证据表明，氟烷诱导的肝损伤至少部分是由于增强了内质网应激和其反应性代谢物三氟乙酰氯共价修饰内质网中的伴侣蛋白而导致的未折叠蛋白反应。

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.