Multidrug resistance-associated protein 2

Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ABCC2 gene.[5][6][7]

ABCC2
Identifiers
AliasesABCC2, ABC30, CMOAT, DJS, MRP2, cMRP, Multidrug resistance-associated protein 2, ATP binding cassette subfamily C member 2
External IDsOMIM: 601107; MGI: 1352447; HomoloGene: 68052; GeneCards: ABCC2; OMA:ABCC2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000392

NM_013806

RefSeq (protein)

NP_000383

NP_038834

Location (UCSC)Chr 10: 99.78 – 99.85 MbChr 19: 43.77 – 43.83 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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MRP2 is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). More specifically, this protein is a member of the MRP subfamily, which is involved in multi-drug resistance. This protein is expressed in the canalicular (apical) part of the hepatocyte and functions in biliary transport. Substrates include anticancer drugs such as vinblastine; therefore, this protein appears to contribute to drug resistance in mammalian cells.

MRP2 is also expressed in the apical membrane of proximal renal tubule endothelial cells where they are involved in the excretion of small organic anions.[8]

MRP2 inhibitors

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Drug Class Indications Source Structure
probenecid uricosuric gout
hyperuricemia
[9]  
furosemide loop diuretic heart failure
edema
[9]  
ritonavir protease inhibitor antiretroviral [10]  
saquinavir protease inhibitor antiretroviral [11]  
lamivudine Nucleoside analog antiviral [12]  
abacavir Nucleoside analog antiretroviral [12]  
emtricitabine Nucleoside analog antiviral [12]  
efavirenz NNRTI antiretroviral [12]  
delavirdine NNRTI antiretroviral [12]  
nevirapine NNRTI antiretroviral [12]  
cidofovir nucleoside phosphonate antiviral [13]  
adefovir nucleoside phosphonate antiviral [11]  
tenofovir nucleoside phosphonate antiviral [12]  

Clinical significance

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Dubin–Johnson syndrome

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Several different mutations in this gene have been observed in patients with Dubin–Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia.[7][14]

Iatrogenic Fanconi syndrome

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Many negatively charged metabolic waste products are eliminated from the body by the kidneys. These organic anions are transported from the blood into the endothelial cells of the renal proximal tubules by the OAT1 transporter. From there, these waste molecules are transported into the lumen of the tubule by the MRP2 transporter. Many drugs are eliminated from the body by this mechanism. Some of these drugs pass through the MRP2 transporter slowly. This may cause a buildup of organic anions in the cytoplasm of the cells.

Drugs that inhibit the MRP2 transporter can cause a buildup of organic anions inside renal proximal tubule cells. If some of these organic anions inhibit mitochondrial DNA synthesis, it may cause iatrogenic Fanconi syndrome. The nucleoside phosphonate adefovir is a MRP2 inhibitor that has been linked to kidney disease.[15] Tenofovir[16] and cidofovir[17] are also nucleoside phosphonates that inhibit MRP2 and have been associated with Fanconi syndrome.

Interactive pathway map

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Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Irinotecan Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000023839Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025194Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, Kagotani K, Okumura K, Akiyama S, Kuwano M (Oct 1996). "A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation". Cancer Res. 56 (18): 4124–9. PMID 8797578.
  6. ^ van Kuijck MA, Kool M, Merkx GF, Geurts van Kessel A, Bindels RJ, Deen PM, van Os CH (Sep 1997). "Assignment of the canalicular multispecific organic anion transporter gene (CMOAT) to human chromosome 10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization". Cytogenet Cell Genet. 77 (3–4): 285–7. doi:10.1159/000134599. PMID 9284939. S2CID 46739365.
  7. ^ a b "Entrez Gene: ABCC2 ATP-binding cassette, sub-family C (CFTR/MRP), member 2".
  8. ^ Sekine T, Miyazaki H, Endou H (February 2006). "Molecular physiology of renal organic anion transporters". Am. J. Physiol. Renal Physiol. 290 (2): F251–61. doi:10.1152/ajprenal.00439.2004. PMID 16403838.
  9. ^ a b Bakos E, Evers R, Sinkó E, Váradi A, Borst P, Sarkadi B (April 2000). "Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions". Mol. Pharmacol. 57 (4): 760–8. doi:10.1124/mol.57.4.760. PMID 10727523.
  10. ^ Peyrière H, Reynes J, Rouanet I, et al. (March 2004). "Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases". J. Acquir. Immune Defic. Syndr. 35 (3): 269–73. doi:10.1097/00126334-200403010-00007. PMID 15076241.
  11. ^ a b Gimenez F, Fernandez C, Mabondzo A (June 2004). "Transport of HIV protease inhibitors through the blood–brain barrier and interactions with the efflux proteins, P-glycoprotein and multidrug resistance proteins". J. Acquir. Immune Defic. Syndr. 36 (2): 649–58. doi:10.1097/00126334-200406010-00001. PMID 15167283. S2CID 6030800.
  12. ^ a b c d e f g Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE (March 2007). "Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors". Drug Metab. Dispos. 35 (3): 340–4. doi:10.1124/dmd.106.012765. PMID 17172311. S2CID 46141353.
  13. ^ Miller DS (November 2001). "Nucleoside phosphonate interactions with multiple organic anion transporters in renal proximal tubule". J. Pharmacol. Exp. Ther. 299 (2): 567–74. PMID 11602668.
  14. ^ Morii K, Yamamoto T (2016-07-06). "Dubin–Johnson Syndrome". New England Journal of Medicine. 375 (1): e1. doi:10.1056/nejmicm1509529. PMID 27406372.
  15. ^ Marcellin P, Chang TT, Lim SG, et al. (February 2003). "Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B". N. Engl. J. Med. 348 (9): 808–16. doi:10.1056/NEJMoa020681. PMID 12606735.
  16. ^ Atta MG, Fine DM (March 2009). "Editorial comment: tenofovir nephrotoxicity--the disconnect between clinical trials and real-world practice". AIDS Read. 19 (3): 118–9. PMID 19334329.
  17. ^ Vittecoq D, Dumitrescu L, Beaufils H, Deray G (August 1997). "Fanconi syndrome associated with cidofovir therapy". Antimicrob. Agents Chemother. 41 (8): 1846. doi:10.1128/AAC.41.8.1846. PMC 164022. PMID 9257778.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.