Multidrug resistance‐associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate

  title={Multidrug resistance‐associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate},
  author={L{\'a}szl{\'o} Homolya and Andr{\'a}s V{\'a}radi and Bal{\'a}zs Sarkadi},
Many endogenous or xenobiotic lipophilic substances are eliminated from the cells by the sequence of oxidation, conjugation to an anionic group (glutathione, glucuronate or sulfate) and transport across the plasma membrane into the extracellular space. The latter step is mediated by integral membrane glycoproteins belonging to the superfamily of ATP‐Binding Cassette (ABC) transporters. A subfamily, referred as ABCC, includes the famous/infamous cystic fibrosis transmembrane regulator (CFTR… 

The ABC Transporters MDR1 and MRP2: Multiple Functions in Disposition of Xenobiotics and Drug Resistance

This work reviews the function of the human multidrug resistance protein MDR1, (P‐glycoprotein, ABCB1) and the multi-drug resistance protein MRP2 (ABCC2) and focuses on four topics namely structure and physiological functions of these transporters, substrates e.g., drugs, xenotoxins, and environmental toxicants including their conjugates, drug–drug interactions, and the role of chemosensitizers.

Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition

The structure and function of MRP2, the substrates transported and the clinical relevance of MRp2 are focused on.

Physiological, pharmacological and clinical features of the multidrug resistance protein 2.

Expression of drug efflux transporters in poultry tissues.

New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition

This review examines how ABCC2 and ABCC3 are coordinately regulated at the transcriptional level by members of the nuclear receptor (NR) family of ligand-modulated transcription factors and how this can be therapeutically exploited.

Role of MRP transporters in regulating antimicrobial drug inefficacy and oxidative stress-induced pathogenesis during HIV-1 and TB infections

The prime objective of this review is to delineate the role of MRP transporters in HAART and TB therapy and their potential in precipitating cellular dysfunctions manifested in these chronic infectious diseases.

The multidrug resistance protein 1 (Mrp1), but not Mrp5, mediates export of glutathione and glutathione disulfide from brain astrocytes

Data demonstrate that in astrocytes Mrp1 mediates 60% of the GSH export, thatMrp1 is exclusively responsible for GSSG export and that Mrp5 does not contribute to these transport processes.

Non-destructive micromethod for MRP1 functional assay in human lung tumor cells

Experiments on the transport activity of MRP1 in cultured human lung tumor cells confirm that MRP 1 function can be followed in the attached cells in vitro under non-toxic concentrations of the substrates without the need to harvest and destroy the cells.



Export pumps for glutathione S-conjugates.

  • D. Keppler
  • Biology
    Free radical biology & medicine
  • 1999

Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump.

It is established that MRP functions as an ATP-dependent export pump not only for glutathione conjugates but also for glucuronidated and sulfated endogenous as well as exogenous compounds.

ATP-dependent transport of aflatoxin B1 and its glutathione conjugates by the product of the multidrug resistance protein (MRP) gene.

It is demonstrated that MRP is capable of energy-dependent transport of aflatoxin B1 and its GSH conjugates and suggest a potential protective role for MRP in mammalian chemical carcinogenesis.

A family of drug transporters: the multidrug resistance-associated proteins.

Whether long-term inhibition of MRPs in humans can be tolerated (assuming that suitable inhibitors will be found) remains to be determined.

Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs.

  • J. WijnholdsC. Mol P. Borst
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
It is speculated that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients.

Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane

The results indicate that the basolateral MRP isoform, MRP3, may be upregulated when the canalicular secretion of anionic conjugates by MRP2 is impaired.

MRP3, an organic anion transporter able to transport anti-cancer drugs.

MRP3 is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2, and in Madin-Darby canine kidney II cells, MRP3 routes to the basolateral membrane and mediates transport of the organicAnion S-(2,4-dinitrophenyl-)glutathione toward the basoliateral side of the monolayer.

Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport.

  • M. MüllerC. Meijer P. Jansen
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
It is demonstrated that overexpression of the MRP gene in human cancer cells increases the ATP-dependent glutathione S-conjugate carrier activity in plasma membrane vesicles isolated from these cells, suggesting that MRP can cause multidrug resistance by promoting the export of drug modification products from cells.


The identification of the MRPs and the demonstration of a central role for ABC transporters, in general, in plant function not only provide fresh insights into the molecular basis of energy-dependent solute transport but also offer the prospect for manipulating and investigating many fundamental processes that have hitherto evaded analysis at the transport level.