Overview: Impact of MRP2 on Toxicology

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