Regulation of Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) and Its Role in Drug Disposition

Abstract

The multidrug resistance protein 2 (MRP2; ABCC2) is an ATPbinding cassette transporter accepting a diverse range of substrates, including glutathione, glucuronide, and sulfate conjugates of many endo-and xenobiotics. MRP2 generally performs excretory or protective roles, and it is expressed on the apical domain of hepatocytes, enterocytes of the proximal small intestine, and proximal renal tubular cells, as well as in the brain and the placenta. MRP2 is regulated at several levels, including membrane retrieval and reinsertion, translation, and transcription. In addition to transport of conjugates, MRP2 transports cancer chemotherapeutics, uricosurics, antibiotics, leukotrienes, glutathione, toxins, and heavy metals. Several mutagenesis studies have described critical residues for substrate binding and various naturally occurring mutations that eliminate MRP2 expression or function. MRP2 is important clinically as it modulates the pharmacokinetics of many drugs, and its expression and activity are also altered by certain drugs and disease states.

Interaction of Positional Isomers of Quercetin Glucuronides with the Transporter ABCC2 (cMOAT, MRP2)

“…Recent studies suggest that ABCC2 influences oral bioavailability (Dietrich et al, 2003), and its inhibition decreases the elimination of xenobiotics. It is structurally closely related to ABCC1 (MRP1) and the substrate selectivities of ABCC1 and ABCC2 overlap (Gerk and Vore, 2002) to a large extent.The 1545-amino acid human ABCC2 contains two nucleotidebinding domains and up to 17 transmembrane helices distributed within three transmembrane domains (TMD), 1, 2, and 3. Classified in the same MRP family, human ABCC1 and human ABCC2 share 48% sequence identity as well as a similar membrane topology, implying structural and functional similarity.…”

Regorafenib Is Transported by the Organic Anion Transporter 1B1 and the Multidrug Resistance Protein 2

“…4) MRP2 is important clinically because it modulates the pharmacokinetics of many drugs, and its expression and activity are also altered by certain drugs and disease states. 5) Organic anion transporting polypeptides (OATPs) belong to the superfamily of solute carrier transporters and are classified within the solute carrier of the OATPs (SLCO) gene family. OATPs function in the uptake of a wide range of amphipathic compounds by cells, including numerous endo-and xenobiotics.…”

The Blood-Brain Barrier in Epilepsy

“…The authors showed that UGT metabolised 1-naphthol in situ into a glucurono-conjugate (phase II) that was excreted by an efflux transporter (phase III). In this regard, MRPs have been implicated in cellular export of various glutathione, glucuronide, and sulfate conjugates compounds, and several other endogenous and xenobiotic compounds (Gerk & Vore, 2002;Jedlitschky et al, 1996;Loe et al, 1996;Oude Elferink & Jansen, 1994). Although Mrp involvement has not directly been shown in Strazielle and Ghersi-Egea's study, Mrp-mediated efflux of the 1-naphthol glucurono-conjugate seems likely as the export was sensitive to the Mrp inhibitor probenecid.…”