Overview: Impact of MRP2 on Toxicology

M. Vore
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Abstract

The identification of the family of multidrug-resistance-associated proteins (MRPs) has provided new understanding regarding mechanisms of absorption, distribution, elimination, and toxicity of both endoand xenobiotics. Just over 10 years ago, Cole et al. (1) identified MRP1, the founding member of this family, in a multidrug-resistant human lung cancer cell line that did not express MDR1 P-glycoprotein. This issue of Comments on Toxicology is devoted to three topics related to MRP2, the second member of this family to be identified, and the role it plays in both mediating and protecting against toxicity. MRP2 (ABCC2) is the transporter that mediates the biliary excretion of numerous drugs and their metabolites. The first article by Christoph Dietrich and colleagues, details several examples in which MRP2 protects the organism from toxicity by preventing the absorption of dietary carcinogens and, conversely, promotes toxicity of chemicals, such as a-naphthylisothiocyanate, by eliminating them from the hepatocyte but concentrating them in bile, where they then induce local damage to cholangiocytes, the cells lining the biliary tree. The article by Ned Ballatori and colleagues summarizes the evidence demonstrating that MRP2 mediates the secretion of glutathione (GSH) into bile, which contributes significantly to the generation of bile flow. MRP2-mediated transport of GSH, either alone or as a part of a complex, is a two-edged sword, resulting in protection of cholangiocytes and enterocytes downstream from the hepatocyte, but also in depletion of the hepatocyte of GSH under certain conditions, such as in the presence of arsenite. MRP2-mediated efflux of GSH
综述:MRP2对毒理学的影响
多药耐药相关蛋白(MRPs)家族的鉴定为内源性和外源性抗生素的吸收、分布、消除和毒性机制提供了新的认识。就在10多年前,Cole等人(1)在一种不表达MDR1 p -糖蛋白的多药耐药人肺癌细胞系中发现了该家族的创始成员MRP1。本期《毒理学评论》专门讨论与MRP2相关的三个主题,MRP2是该家族的第二个成员,它在介导和保护毒性方面发挥的作用。MRP2 (ABCC2)是介导多种药物及其代谢物胆汁排泄的转运蛋白。Christoph Dietrich及其同事的第一篇文章详细介绍了几个例子,其中MRP2通过阻止饮食致癌物的吸收来保护生物体免受毒性,相反,通过将化学物质(如a-naphthylisothiocyanate)从肝细胞中清除,但将其集中在胆汁中,从而促进化学物质(如a-naphthylisothiocyanate)的毒性,然后在胆汁中诱导胆管细胞(胆树的细胞)局部损伤。Ned Ballatori及其同事的文章总结了MRP2介导谷胱甘肽(GSH)分泌到胆汁中的证据,这对胆汁流动的产生有重要作用。mrp2介导的GSH运输,无论是单独的还是作为复合物的一部分,都是一把双刃剑,导致肝细胞下游的胆管细胞和肠细胞受到保护,但在某些条件下,如在亚砷酸盐存在的情况下,也会导致肝细胞的GSH消耗。mrp2介导的谷胱甘肽外排
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