Hepatoprotective Mrp3

描述（由申请人提供）：本项目的目的是确定Mrp 3的药理学诱导是否可用作胆汁淤积性疾病状态下人类肝脏保护的一种手段。mrp 3通常以低水平表达，用于将多种有机阴离子从肝脏输出回到血液，从而降低其对肝脏的暴露和毒性。mrp 3的表达显着增加，在响应某些微粒体酶诱导剂，以及在啮齿动物胆汁淤积。Mrp 3的人类表达在某些肝脏疾病中也增加。在小鼠和大鼠中，某些微粒体酶诱导剂可显著增加mrp 3的表达。然而，Mrp 3的诱导机制似乎是一个复杂的相互作用，在体外进行的转录研究无法准确地复制在体内观察到的诱导。目的1和2旨在确定人Mrp 3表达是否可以通过这种相同的机制来诱导。这些是; 1.确定Mrp 3表达的胆汁淤积和药理学诱导的共同机制。2.使用独特的转录激活试验和人肝切片确定是否可以在体内诱导人Mrp 3基因。胆汁淤积是一种非常复杂的疾病，具有多种病因，导致胆汁酸和其他有机阴离子的积累，从而引起严重的肝细胞损伤。如果Mrp 3可以在人体中被诱导，作为消除肝脏暴露于积累胆汁酸和其他有机阴离子的毒性作用的一种手段，这将代表胆汁淤积期间肝脏保护的一种重要手段。目的3和4旨在确定Mrp 3诱导是否可用作治疗人类肝脏疾病的合法药物靶标。这些是; 3。确定增加Mrp 3表达的微粒体酶诱导剂是否能够改变胆汁成分的分布并在胆汁淤积期间保护肝毒性。4.确定人Mrp 3的转基因过表达是否在胆汁淤积模型中具有保肝作用。

DESCRIPTION (PROVIDED BY APPLICANT: The goal of this project is to determine whether pharmacologic induction of Mrp3 can be used as a means of hepatoprotection in humans during cholestatic disease states. Mrp3, which is normally expressed at low levels, serves to export a wide range of organic anions from the liver, back to the blood, thereby decreasing their exposure and toxicity to the liver. Mrp3 expression is significantly increased both in response to certain microsomal enzyme inducers as well as during cholestasis in rodents. Human expression of Mrp3 is also increased in certain liver diseases. Mrp3 expression can be pharmacologically increased by certain microsomal enzyme inducers in both mouse and rat. However, the mechanism for the induction of Mrp3 appears to be a complex interaction where transcriptional studies performed in vitro are unable to accurately replicate the induction observed in vivo. Aims 1 and 2 are designed to determine whether human Mrp3 expression can be pharmacologically induced by this same mechanism. These are; 1. Determine the common mechanism for the cholestatic and pharmacologic induction of Mrp3 expression. 2. Determine whether the human Mrp3 gene can be induced in vivo using a unique transcriptional activation assay and human liver slices. Cholestasis is a very complex disease with multiple etiologies that results in the accumulation of bile acids and other organic anions that cause profound hepatocellular damage. If Mrp3 can be pharmacologically induced in humans as a means of eliminating hepatic exposure to the toxic effects of accumulating bile acids and other organic anions, this would represent an important means of hepatoprotection during cholestasis. Aims 3 and 4 have been designed to determine whether Mrp3 induction can be used as a legitimate drug target in the treatment of human liver disease. These are; 3. Determine whether microsomal enzyme inducers that increase expression of Mrp3 are capable of altering the disposition of biliary constituents and protecting against hepatotoxicity during cholestasis. 4. Determine whether the transgenic overexpression of human Mrp3 is hepatoprotective in models of cholestasis.