REGULATION OF BILIARY EXCRETION OF XENOBIOTICS BY MRP2

MRP2 对异生物质胆汁排泄的调节

• 批准号: 6607711
• 负责人: CURTIS D KLAASSEN
• 金额: $ 30万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607711
• 关键词: DNA footprinting; biliary tract; biological transport; cytochrome P450; detoxification; drug metabolism; enzyme activity; excretion; fluorescence microscopy; gel mobility shift assay; high performance liquid chromatography; laboratory rat; molecular cloning; multidrug resistance; nuclear runoff assay; phosphorylation; protein kinase; protein structure function; receptor expression; second messengers; tissue /cell culture; toxin metabolism; western blottings

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.

描述（改编自申请人摘要）：生物转化和 异生物质、药物和化学品的解毒本质上是 这取决于生物体排泄这些化合物的能力。排泄 系统可被化疗剂上调， 在许多癌症中观察到多药耐药性。化疗诱导药物 耐药性是由于运输化学物质的蛋白质的过度表达 从癌细胞中分离出来这些蛋白质包括P-糖蛋白和 多药耐药蛋白（Mrp），由多种药物编码， 耐药基因（MDR）和mrp基因。在正常肝脏中， 肝小管膜转运蛋白的定位 实质细胞对于输出/排泄 化学物质进入胆汁。mrp基因家族的一个成员，Mrp2（以前的cMOAT）， 是一种ATP依赖性小管转运蛋白，负责 排泄各种有机阴离子，包括谷胱甘肽，硫酸盐， 化学品和异生物质的葡糖苷酸缀合物。这些运输过程， 其中MRP 2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。这第三个人 生物转化阶段可以与阶段I和阶段II协调调节， 和II系统对化学刺激的反应很有趣，并表明 生物转化的所有三个阶段都是耦合的， 肝细胞代谢/化学品解毒的效率。这 实验室已经报道了化学物质增加肝胆的能力， 功能，我们假设这是内在相关的Mrp2表达和 功能前两个目标将测试假设，这些观察 是由于III期代谢的改变，更具体地说是Mrp2的改变 调控这个实验室发表了大量的研究成果 表明新生动物体内的化学物质毒性显著增加， 这是由于化学诱导的肝胆功能增强。目标3 应用程序将测试化学引起的成熟的假设， 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 相互作用可引起肝排泄载体的转变， 减少肝胆排泄和增加肝血管排泄。目标4 将检验这一假设，即肝脏排泄的这种转变是由于 Mrp2在肝胆管中的化学诱导差异表达 膜和Mrp3在窦膜上。最后一个目标测试了一个完全 药物代谢的新概念和胆汁中蛋白质的调控 排泄，也就是说，Mrp2是由一个孤儿核受体， 胆甾烷X受体。阐明控制Mrp2介导的 排泄药物将继续启发科学和医学 生物外源性物质运输过程的重要性， 创造安全和生物活性的药物， 运输缺陷和保护公众免受化学品接触。