Multiple Mechanisms of Hepatoprotective Mrp3 Induction

Mrp3 诱导的保肝多重机制

基本信息

批准号：
6893444
负责人：
Nathan J Cherrington
金额：
$ 10.79万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-18 至 2007-06-30
项目状态：
已结题

项目摘要

The goal of this project is to determine the mechanism(s) by which Mrp3 is transcriptionally activated in a hepatoprotective response. Mrp3, which is localized to the sinusoidal membrane of hepatocytes, exports a wide range of I organic anions from the liver, into the blood. Thus, the role of hepatic Mrp3 is to decrease the concentration of potentially toxic molecules in the liver. Mrp3 expression is normally low in liver but is significantly increased after exposure to certain inducers and also during cholestasis, further demonstrating the importance of Mrp3-mediated export as a means of hepatoprotection. Cholestatic liver injury results in a substantial clinical burden leading to an estimated 100,000 deaths per year often listed as multiple organ dysfunction. The current clinical management of chotestasis includes phenobarbital, which decreases hepatotoxicity as a side effect of cholestasis. I have previously demonstrated that treatment with multiple reducers of CYP2B 1/2, (transcriptionally activated by CAR) such as phenobarbital, as well as inducers of NADP(H):quinone oxidoreductase (activated through Nrf2) are also capable of inducing Mrp3, showing coordinate regulation of both the Phase I drug-metabolizing genes and Phase III xenobiotic transporters. It has also been demonstrated that cholestasis results in increased Mrp3 but decreased CYP2B 1/2 levels suggesting distinct mechanisms involved in the regulation of Mrp3. Additionally, other outcomes of cholestasis include an increase in oxidative stress, hyperbilirubinemia, inflammation and cytokine releasc, all of which, individually, effect the regulation of xenobiotic transporters or Phase I drug metabolizing genes in a manner consistent with the effects of cholestasis. Therefore, the following aims have been designed to test the hypothesis that Mrp3 is differentially regulated during periods of both chemical insult and cholestatic stress: 1) Determine the role of the Constitutive Androstane Receptor in transcriptional activation by microsomal enzyme inducers that activate Mrp3 expression. 2) Determine whether the induction of Mrp3 during cholestasis is mediated by either prooxidant or antioxidant activation of Nrf2.3) Determine whether cytokine release, signaling, and NF-kB activation are responsible for the differential regulation of Mrp3 during cholestasis. 4) Define the Mrp3 promoter elements that are responsible for the transcriptional activation during both chemical insult and cholestatic stress. Understanding the mechanisms that control Mrp3-mediated excretion of organic anions can potentially serve the scientific community in our objective to create safe and biologically active drugs that alleviate specific transport deficiencies or up-regulate the excretion of chemicals in patients or exposed individuals.

该项目的目的是确定MRP3在肝保护反应中转录激活的机制。 MRP3位于肝细胞的正弦膜上，将各种有机阴离子从肝脏中导出到血液中。因此，肝MRP3的作用是降低肝脏中潜在毒性分子的浓度。 MRP3表达通常低于肝脏，但在暴露于某些诱导剂以及胆汁淤积过程中也显着增加，进一步证明了MRP3介导的出口作为肝保护的一种手段的重要性。胆汁淤积性肝损伤导致巨大的临床负担，导致每年估计有100,000例死亡通常被列为多个器官功能障碍。当前的链球菌临床管理包括苯巴比妥，这降低了肝毒性作为胆汁淤积的副作用。我以前已经证明了用CYP2B 1/2的多个还原器（通过汽车激活的转录激活）以及NADP（H）的诱导剂（H）：喹酮氧化还原酶（通过NRF2激活）也能够诱导MRP3，表明对I期药物对基因的坐标调节均可诱导MRP3，并能够诱导MRP3。还证明胆汁淤积会导致MRP3增加，但CYP2B 1/2水平降低，表明MRP3调节涉及的不同机制。此外，胆汁淤积的其他结果包括氧化应激，高胆红素血症，炎症和细胞因子释放的增加，所有这些都以与胆汁疾病的影响一致的方式单独影响了异种生物转运蛋白或I期药物代谢基因的调节。因此，已经设计了以下目标来检验假设，即在化学损伤和胆汁淤积应力期间对MRP3受到差异调节：1）确定构型雄激素受体在通过微粒子酶诱导剂转录激活中的作用，从而激活MRP3表达。 2）确定胆汁淤积过程中MRP3的诱导是否是通过NRF2.3的促氧化剂或抗氧化剂激活介导的释放，信号传导和NF-KB激活负责胆汁淤积过程中MRP3的差异调节。 4）定义在化学损伤和胆汁淤积应力期间负责转录激活的MRP3启动子元件。了解控制MRP3介导的有机阴离子排泄的机制可以潜在地为我们目标的科学界服务，以创建缓解安全和生物活性的药物以减轻特定的运输缺陷或上调患者或暴露个体的化学物质排泄。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats.

DOI：
10.1016/j.ejphar.2009.04.002
发表时间：
2009-06-24
期刊：
European journal of pharmacology
影响因子：
5
作者：
Fisher CD;Lickteig AJ;Augustine LM;Oude Elferink RP;Besselsen DG;Erickson RP;Cherrington NJ
通讯作者：
Cherrington NJ

Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes.

拟除虫菊酯：人肝细胞中的细胞毒性和 CYP 异构体的诱导。

DOI：
10.1515/dmdi.2008.23.3-4.211
发表时间：
2008
期刊：
Drug metabolism and drug interactions
影响因子：
0
作者：
Das,ParikshitC;Streit,TimothyM;Cao,Yan;Rose,RandyL;Cherrington,Nathan;Ross,MatthewK;Wallace,AndrewD;Hodgson,Ernest
通讯作者：
Hodgson,Ernest

Pesticide metabolism in humans, including polymorphisms.

人类的农药代谢，包括多态性。