Hepatoprotective Mrp3

描述(由申请人提供：本项目的目标是确定在胆汁淤积性疾病状态下，MRP3的药理诱导是否可以用作人类肝脏保护的一种手段。MRP3通常在低水平表达，用于将多种有机阴离子从肝脏输出到血液中，从而减少它们对肝脏的暴露和毒性。在啮齿类动物的胆汁淤积过程中，在某些微粒体酶诱导剂的作用下，MRP3的表达都显著增加。在某些肝病中，人类mrp3的表达也会增加。在小鼠和大鼠体内，某些微粒体酶诱导剂都能在药理上增加mrp3的表达。然而，MRP3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不能准确地复制在体内观察到的诱导。目标1和目标2旨在确定是否可以通过这种相同的机制在药物上诱导人类mrp3的表达。这些是：1.确定胆汁淤积和药物诱导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，确定是否可以在体内诱导人类mrp3基因。胆汁淤积症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积累，从而导致严重的肝细胞损害。如果在人体中能够通过药物诱导MRP3，以消除肝脏暴露在累积胆汁酸和其他有机阴离子的毒性影响中，这将是在胆汁淤积期间保护肝脏的重要手段。AIMS 3和4的设计目的是确定MRP3诱导是否可以作为治疗人类肝病的合法药物靶点。这些是；3.确定增加MRP3表达的微粒体酶诱导剂是否能够改变胆汁成分的处置，并在胆汁淤积过程中保护肝毒性。4.确定人MRP3转基因过表达对胆汁淤积症动物模型是否具有保肝作用。

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.