REGULATION OF BILIARY EXCRETION OF XENOBIOTICS BY MRP2

描述(改编自申请人的摘要)：生物转化和 外源物质、药物和化学品的解毒本质上是 取决于生物体排泄这些化合物的能力。排泄物 系统可被化疗药物上调在以下现象中 在许多癌症中观察到多药耐药性。化疗药物 抗药性是由于运输化学物质的蛋白质过度表达所致。 从癌细胞中排出。这些蛋白质包括P-糖蛋白和 多种药物编码的多药耐药蛋白(MRP) 耐药基因(Mdr)和mrp基因。在正常肝脏中， 转运蛋白在肝小管膜中的定位 实质细胞在生理上对输出/排泄 将化学物质转化为胆汁。MRP基因家族的成员之一，mrp2(以前的cmoat)， 是一种依赖于ATP的小管转运蛋白，负责 排泄各种有机阴离子，包括谷胱甘肽、硫酸盐和 葡萄糖醛酸苷化学物质和外源化合物的结合物。这些运输过程， 其中MRP2是一个关键组成部分，现在被认为是“第三阶段” 药物/化学肝脏代谢过程。这三分之一的可能性 生物转化的阶段可以与两个阶段协调调节 和II系统对化学刺激的反应是耐人寻味的，并表明 生物转化的所有三个阶段结合在一起，以增加 肝细胞代谢/化学物质解毒的效率。这 实验室已经报道了化学物质增加肝胆的能力 函数，我们假设该函数与mrp2表达式和 功能。前两个目标将检验这样一个假设，即这些观测 是由于III期新陈代谢的改变，更具体地说是改变了MRP2 监管。这个实验室发表了大量的研究成果。 表明化学物质对新生动物的毒性显著增加 由于化学诱导的肝胆功能增强。目标3 应用程序将检验化学诱导的细胞成熟的假设 新生儿肝胆功能是由于MRP2功能增强和/或 表情。此外，该实验室报告说，化学-化学物质 相互作用可导致肝脏排泄向量的转变 减少肝胆排泄，增加肝血管排泄。目标4 将检验这样一种假设，即肝脏排泄的这种转变发生在 对化学诱导的肝胆管组织MRP2差异表达的影响 膜和正弦波膜上的MRP3。最后一个目标是测试一个完全 药物代谢与胆道相关蛋白质调控的新概念 排泄，也就是说，mrp2受一种孤儿核受体 孕烷X受体。MRP2基因调控机制的阐明 排泄的药物将继续启迪着科学和医学 关于外来生物运输过程在以下方面的重要性 到创造安全和生物活性的药物来缓解特定的 交通缺陷和保护公众免受化学物质接触。

DESCRIPTION ( Adapted from the applicant's abstract): Biotransformation and detoxication of xenobiotics, pharmaceuticals, and chemicals is intrinsically dependent on the organism's capacity to excrete these compounds. The excretory systems can be upregulated by chemotherapeutic agents in the phenomenon of multidrug resistance observed in many cancers. Chemotherapy-induced drug resistance is due to the overexpression of proteins which transport chemicals out of cancer cells. These proteins include P-glycoprotein and multidrug-resistance proteins (Mrp) which are encoded by the multiple drug resistance gene (MDR) and the mrp genes, respectively. In normal liver, localization of transport proteins in the canalicular membrane of hepatic parenchymal cells is physiologically important for export/excretion of chemicals into bile. One member of the mrp gene family, Mrp2 (formerly cMOAT), is an ATP-dependent canalicular transporter protein responsible for the excretion of various organic anions, including glutathione, sulfate, and glucuronide conjugates of chemicals and xenobiotics. These transport processes, of which Mrp2 is a critical component, are now considered the "phase III" process of drug/chemical hepatic metabolism. The possibility that this third phase of biotransformation can be regulated in coordination with both phase I and II systems in response to chemical stimuli is intriguing and would suggest that all three phases of biotransformation are coupled to increase the efficiency of hepatocellular metabolism/detoxication of chemicals. This laboratory has reported on the ability of chemicals to increase hepatobiliary function, which we postulate to be intrinsically related to Mrp2 expression and function. The first two aims will test the hypothesis that these observations are due to altered phase III metabolism, more specifically altered Mrp2 regulation. This laboratory has published an extensive amount of research showing that marked increases in toxicity of chemicals in newborn animals occur as a result of chemical-induced enhanced hepatobiliary function. Aim 3 of this application will test the hypothesis that chemical-elicited maturation of neonatal hepatobiliary function is due to enhancement of Mrp2 function and/or expression. Further, this laboratory has reported that chemical-chemical interactions can cause a transition shift in the vector of hepatic excretion to decrease hepatobiliary excretion and increase hepatovascular excretion. Aim 4 will test the hypothesis that this transition in hepatic excretion occurs due to the chemical-induced differential expression of Mrp2 on the hepatobiliary membrane and Mrp3 on the sinusoidal membrane. The last Aim tests an entirely new concept in drug metabolism and control of proteins involved in biliary excretion, that is, that Mrp2 is regulated by an orphan nuclear receptor, the pregnane X receptor. Elucidation of mechanisms that control Mrp2-mediated excretion of drugs will continue to enlighten the scientific and medical communities as to the importance of xenobiotic transport processes in relation to creating safe and biologically active drugs that alleviate specific transport deficiencies and protecting the public from chemical exposure.