Consequences of MRP2 Deficiency: Lessons from Rats with a Mutation in This Exporter

M. Treinen-Moslen, L. Kaphalia, M. F. Kanz
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引用次数: 1

Abstract

MRP2, a multidrug resistance-associated protein, helps to maintain mammalian homeostasis by exporting bilirubin conjugates and many xenobiotics into bile or urine. Experiments with two mutant rat strains, namely TR− and EHBR which have a functionally deficient MRP2, have revealed major alterations in the fate and pathophysiology of substrates for this exporter. Such alterations have clinical implications because multiple conditions, notably sepsis and bile duct obstruction, are associated with diminished expression of the exporter. However, the homeostatic response to MRP2 deficiency is complex since other reported changes in tissues of rats with a mutation in this exporter appear to have compensatory influences on the responses to MRP2 substrates. The goal of this commentary is to describe some representative lessons about the consequences of MRP2 deficiency that have been learned from experiments with the mutant rats. Emphasis will be given to recent observations about the consequences of this deficiency on responses to the NSAID diclofenac, including intestinal ulcers and drug protein adducts in liver, intestine and kidney. Such observations could lead to new strategies for safer therapeutic protocol for drugs whose reactive metabolites are substrates for the MRP2 exporter.
MRP2缺失的后果:从这种出口者突变的大鼠身上得到的教训
MRP2是一种多药耐药相关蛋白,通过将胆红素偶联物和许多外源药物输出到胆汁或尿液中,帮助维持哺乳动物的体内平衡。对MRP2功能缺陷的两种突变大鼠菌株TR -和EHBR进行的实验揭示了这种出口物的底物命运和病理生理的重大改变。这种改变具有临床意义,因为多种情况,特别是败血症和胆管阻塞,与出口蛋白表达减少有关。然而,对MRP2缺乏的稳态反应是复杂的,因为在该输出基因突变的大鼠组织中,其他报道的变化似乎对MRP2底物的反应具有代偿性影响。这篇评论的目的是描述从突变大鼠实验中获得的关于MRP2缺陷后果的一些代表性经验教训。重点将放在最近观察到的这种缺乏对非甾体抗炎药双氯芬酸反应的后果,包括肠溃疡和肝、肠和肾的药物蛋白加合物。这样的观察结果可能会为那些反应性代谢物是MRP2输出物底物的药物提供更安全的治疗方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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