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Multidrug Resistance-Associated Protein 2

Multidrug Resistance-Associated Protein 2

An overview of Multidrug Resistance-Associated Protein 2

Multidrug Resistance-Associated Protein 2 is a protein found in humans encoded by ABCC2 gene. It is also known as canalicular multiseptic organic anion transporter and belongs to the ATP binding cassette subfamily c member 2. ABC Multidrug resistance  family of transporters belongs to one of the largest and oldest with members from extant phyla from prokaryotes and is transported to human beings. In medical field, multidrug resistance is widely used to elaborate resistance mechanism that cells have in response to a wide range of chemotherapeutic drugs used in treatment of cancer.

Function of MRP2

MRP2 is an ATP binding cassette of ABC family superfamily. They transport different molecules across intra and extra cellular membranes. ABC genes are classified into a wide range of distinct subfamilies including MDR/TAP, MRP, OAB, GCN20, White and ABC 1. The drug is therefore widely involved in multi drug resistance.

The protein is also highly expressed in the apical part of hepatocyte and operates in biliary transport. It also includes substrates that include different anticancer medications including vinblastine. Therefore, the protein appears to play a major role in resistance in mammalian cells. MRP2 is also expressed on canalicular membrane of proximal renal tubule endothelial cells. In the cells, they carry out excretion of small organic anions.

Following different studies, MRP2 was included into drug resistance family by Susan Cole and Rodger Deeley in 1996. More members were included into the family afterwards and they were considered as canalicular multispecific organic anion transporter following its cloning. Homology is one of the high MRP2 as it is in the case of MRP1, 3 and MRP6. The MRPs also have similar features of TMD0Lo segment. They also play a role in enhancing pump from eukaryotes such as yeast and leishmanial.

MRP2 in mammals also transport methotrexate and appear to function more in the liver, kidney and the gut.

MRP2 Clinical relevance

MRP2 has a major clinical significance in different cases including Iatrogenic Fanconi Syndrome and Dubin-Johnson syndrome. In the latter, several gene mutations have been discovered in patients. Therefore, there is an autosomal recessive abnormality that is characterized by conjugated hyperbilirubinemia.

MRP2 also enhances elimination of wastes from the body. The organic anions are transferred from the blood to endothelial cells by OAT1 transporter. Waste molecules are transferred into lumen of the tubule by the transporter. More drugs are also eliminated from human body by the mechanism.  Therefore, the drugs pass through the MRP2 transporter slowly thus, causing a large buildup of anions in cell cytoplasm.

It is therefore imperative to note that there are different drugs that inhibit MRP2 transporter and they easily cause a buildup of different organic anions in renal proximal tubule cells. If the organic anions inhibit mitochondrial DNA synthesis, they can easily cause iatrogenic Fanconi syndrome. One of the MRP2 inhibitors that has been highly associated or linked to kidney disease is the nucleoside phosphonate adefovir. Cidovir and Tenofovir on the other hand have been linked to Fanconi syndrome.

Multidrug resistance associated protein 2 is also very useful in protection against a wide range of toxic elements and compounds. The availability of various ABC transporters offers a solid defense against toxic elements. Therefore, the discovery of MRP 2 and MRP family at large has enhanced the study of MDR tumor cells. This further led into more interest in the roles and functions of MRP family members in normal metabolism.

Issues related to Multidrug Resistance associated protein 2

There are few issues that have been discovered in MRP2 studies including

  • Availability of inhibitors and antibodies that cross react with members of the MRP2 family. However, monoclonal antibodies that act against parts that are not conserved can be generated to address the issue.
  • Characterization of MRPs, making them organic anion transporters -Therefore, many substrates for the transporters is highly charged and cannot penetrate cell membrane.
  • It is also difficult to get MRP2 transfect-ants therefore; more products are being channeled to cell membrane.
  • Last but not least, body cells that are selected for drug resistance in many cases, over express multiple transporter genes. The good thing is that there are several inhibitors that have been utilized to solve this issue.

 

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Sources

http://jnci.oxfordjournals.org/content/92/16/1295.full

http://www.sciencedirect.com/science/article/pii/S0005273699001674

http://www.sciencedirect.com/science/article/pii/S0014579305014262