CHAPTER 20 – MRP2, THE APICAL EXPORT PUMP FOR ANIONIC CONJUGATES

In the elimination and detoxification of endogenous and xenobiotic substances, the ATP-dependent unidirectional transport of anionic conjugates across the apical membrane domain of polarized cells plays an important role. This transport function was originally described as a glutathione S -conjugate transport system and as a canalicular multispecific organic anion transporter. Subsequent cloning, expression and functional analysis of the recombinant protein has established that the apical conjugate export pump is encoded by the MRP2 ( ABCC2 ) gene. Antibodies raised against various epitopes of MRP2 from several species served to localize the MRP2 glycoprotein to the apical membrane of polarized cells, including hepatocytes, kidney proximal tubules, intestinal epithelia, and lung. The apical localization of MRP2 and its broad substrate specificity for various conjugates qualify this ATP-binding cassette (ABC) transporter as an important terminal component in detoxification, subsequent to the phase I and phase II reactions of xenobiotic metabolism. Mutations and polymorphisms in the human MRP2 gene that affect MRP2 function may be relevant for adverse drug reactions because of an impaired hepatobiliary and renal clearance of anionic drug conjugates. Moreover, such polymorphisms may also affect the oral bioavailability of drugs that are substrates for intestinal MRP2 or become substrates following conjugation inside intestinal epithelia.