Multidrug resistance-associated protein 2

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
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RefSeq (mRNA)

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RefSeq (protein)

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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.[1][2][3]

Function

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.[4]

MRP2 inhibitors

Drug Class Indications Source Structure
probenecid uricosuric gout
hyperuricemia
[5] 100px
furosemide loop diuretic heart failure
edema
[5] 100px
ritonavir protease inhibitor antiretroviral [6] 100px
saquinavir protease inhibitor antiretroviral [7] 100px
lamivudine Nucleoside analog antiviral [8] 100px
abacavir Nucleoside analog antiretroviral [8] 100px
emtricitabine Nucleoside analog antiviral [8] 100px
efavirenz NNRTI antiretroviral [8] 100px
delavirdine NNRTI antiretroviral [8] 100px
nevirapine NNRTI antiretroviral [8] 100px
cidofovir nucleoside phosphonate antiviral [9] 100px
adefovir nucleoside phosphonate antiviral [7] 100px
tenofovir nucleoside phosphonate antiviral [8] 100px

Clinical significance

Dubin-Johnson syndrome

Several different mutations in this gene have been observed in patients with Dubin-Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia.[3][10]

Iatrogenic Fanconi syndrome

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.[11] Tenofovir[12] and cidofovir[13] are also nucleoside phosphonates that inhibit MRP2 and have been associated with Fanconi syndrome.

Interactive pathway map

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_WP46359".

See also

References

  1. 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.
  2. 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.
  3. 3.0 3.1 "Entrez Gene: ABCC2 ATP-binding cassette, sub-family C (CFTR/MRP), member 2".
  4. 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.
  5. 5.0 5.1 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. PMID 10727523.
  6. 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. PMID 15076241.
  7. 7.0 7.1 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.
  8. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 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.
  9. 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.
  10. Morii, Kazuhiko; Yamamoto, Takeharu (2016-07-06). "Dubin–Johnson Syndrome". New England Journal of Medicine. 375 (1): e1. doi:10.1056/nejmicm1509529. PMID 27406372.
  11. 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.
  12. 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.
  13. Vittecoq D, Dumitrescu L, Beaufils H, Deray G (August 1997). "Fanconi syndrome associated with cidofovir therapy". Antimicrob. Agents Chemother. 41 (8): 1846. PMC 164022. PMID 9257778.

Further reading

External links

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


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