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

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.