Hepatoprotective Mrp3

描述（由申请人提供）：该项目的目的是确定在胆汁淤积疾病状态下，Mrp3的药物诱导是否可以作为人类肝脏保护的一种手段。Mrp3在正常情况下表达水平较低，它的作用是将多种有机阴离子从肝脏输出回血液，从而减少它们对肝脏的暴露和毒性。Mrp3的表达在对某些微粒体酶诱导剂的反应中以及在啮齿动物的胆汁淤积期间都显着增加。人在某些肝脏疾病中Mrp3的表达也增加。在小鼠和大鼠中，某些微粒体酶诱导剂均可增加Mrp3的表达。然而，诱导Mrp3的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体内观察到的诱导。目的1和目的2旨在确定人类Mrp3的表达是否可以通过相同的机制从药理学上诱导。这些都是;1. 确定抑制胆固醇和诱导Mrp3表达的共同机制。2. 使用独特的转录激活试验和人肝切片确定人Mrp3基因是否可以在体内诱导。胆汁淤积症是一种非常复杂的疾病，有多种病因，导致胆汁酸和其他有机阴离子的积累，造成严重的肝细胞损伤。如果Mrp3可以在人体中被药理学诱导，作为消除肝脏暴露于胆汁酸和其他有机阴离子积累的毒性作用的一种手段，这将是胆汁淤积期间保护肝脏的重要手段。Aims 3和4旨在确定Mrp3诱导是否可以作为治疗人类肝脏疾病的合法药物靶点。这些都是;3. 确定增加Mrp3表达的微粒体酶诱导剂是否能够改变胆道成分的配置，并在胆汁淤积期间防止肝毒性。4. 确定转基因过表达人Mrp3在胆汁淤积模型中是否具有肝保护作用。

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.