Multidrug resistance-associated protein 2

Protein found in humans
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
Gene location (Human)
Chromosome 10 (human)
Chr.Chromosome 10 (human)[1]
Chromosome 10 (human)
Genomic location for ABCC2
Genomic location for ABCC2
Band10q24.2Start99,782,640 bp[1]
End99,852,594 bp[1]
Gene location (Mouse)
Chromosome 19 (mouse)
Chr.Chromosome 19 (mouse)[2]
Chromosome 19 (mouse)
Genomic location for ABCC2
Genomic location for ABCC2
Band19 C3|19 36.67 cMStart43,770,631 bp[2]
End43,829,179 bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • right lobe of liver

  • jejunal mucosa

  • gallbladder

  • duodenum

  • human kidney

  • mucosa of ileum

  • testicle

  • tibial nerve

  • gonad

  • sural nerve
Top expressed in
  • left lobe of liver

  • duodenum

  • right kidney

  • proximal tubule

  • jejunum

  • human kidney

  • yolk sac

  • epithelium of small intestine

  • ileum

  • migratory enteric neural crest cell
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
  • ATPase activity
  • nucleotide binding
  • protein binding
  • ATP binding
  • transporter activity
  • protein domain specific binding
  • ATPase-coupled transmembrane transporter activity
  • organic anion transmembrane transporter activity
  • ATPase-coupled inorganic anion transmembrane transporter activity
  • bilirubin transmembrane transporter activity
  • transmembrane transporter activity
Cellular component
  • integral component of membrane
  • membrane
  • cell surface
  • plasma membrane
  • apical plasma membrane
  • brush border membrane
  • intercellular canaliculus
  • integral component of plasma membrane
Biological process
  • response to steroid hormone
  • response to arsenic-containing substance
  • prostaglandin transport
  • response to methotrexate
  • thyroid hormone transport
  • xenobiotic transmembrane transport
  • transmembrane transport
  • cellular chloride ion homeostasis
  • response to oxidative stress
  • response to estrogen
  • response to heat
  • bilirubin transport
  • female pregnancy
  • mercury ion transport
  • canalicular bile acid transport
  • antibiotic metabolic process
  • cellular response to lipopolysaccharide
  • cellular response to interleukin-1
  • cellular response to interleukin-6
  • cellular response to tumor necrosis factor
  • cellular response to dexamethasone stimulus
  • response to antineoplastic agent
  • benzylpenicillin metabolic process
  • cellular response to hormone stimulus
  • transport
  • organic anion transport
  • response to lipopolysaccharide
  • response to glucagon
Sources:Amigo / QuickGO
Orthologs
SpeciesHumanMouse
Entrez

1244

12780

Ensembl

ENSG00000023839

ENSMUSG00000025194

UniProt

Q92887

Q8VI47

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

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]

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.[8]

MRP2 inhibitors

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

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.[7][14]

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.[15] Tenofovir[16] and cidofovir[17] 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]

[[File:
IrinotecanPathway_WP46359go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
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IrinotecanPathway_WP46359go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
|alt=Irinotecan Pathway edit]]
Irinotecan Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000023839 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025194 – Ensembl, 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

  • Keppler D, König J (2001). "Hepatic secretion of conjugated drugs and endogenous substances". Semin. Liver Dis. 20 (3): 265–72. doi:10.1055/s-2000-9391. PMID 11076395. S2CID 25626705.
  • Gerk PM, Vore M (2002). "Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition". J. Pharmacol. Exp. Ther. 302 (2): 407–15. doi:10.1124/jpet.102.035014. PMID 12130697. S2CID 873234.
  • Mayer R, Kartenbeck J, Büchler M, et al. (1995). "Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes". J. Cell Biol. 131 (1): 137–50. doi:10.1083/jcb.131.1.137. PMC 2120605. PMID 7559771.
  • Büchler M, König J, Brom M, et al. (1996). "cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats". J. Biol. Chem. 271 (25): 15091–8. doi:10.1074/jbc.271.25.15091. PMID 8662992.
  • Paulusma CC, Kool M, Bosma PJ, et al. (1997). "A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome" (PDF). Hepatology. 25 (6): 1539–42. doi:10.1002/hep.510250635. PMID 9185779. S2CID 22635775.
  • Wada M, Toh S, Taniguchi K, et al. (1998). "Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome". Hum. Mol. Genet. 7 (2): 203–7. doi:10.1093/hmg/7.2.203. PMID 9425227.
  • Evers R, Kool M, van Deemter L, et al. (1998). "Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA". J. Clin. Invest. 101 (7): 1310–9. doi:10.1172/JCI119886. PMC 508708. PMID 9525973.
  • Kajihara S, Hisatomi A, Mizuta T, et al. (1999). "A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome". Biochem. Biophys. Res. Commun. 253 (2): 454–7. doi:10.1006/bbrc.1998.9780. PMID 9878557.
  • Toh S, Wada M, Uchiumi T, et al. (1999). "Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome". Am. J. Hum. Genet. 64 (3): 739–46. doi:10.1086/302292. PMC 1377791. PMID 10053008.
  • Schaub TP, Kartenbeck J, König J, et al. (1999). "Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma". J. Am. Soc. Nephrol. 10 (6): 1159–69. doi:10.1681/ASN.V1061159. PMID 10361853.
  • Tsujii H, König J, Rost D, et al. (1999). "Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome". Gastroenterology. 117 (3): 653–60. doi:10.1016/S0016-5085(99)70459-2. PMID 10464142.
  • Kocher O, Comella N, Gilchrist A, et al. (1999). "PDZK1, a novel PDZ domain-containing protein up-regulated in carcinomas and mapped to chromosome 1q21, interacts with cMOAT (MRP2), the multidrug resistance-associated protein". Lab. Invest. 79 (9): 1161–70. PMID 10496535.
  • Tanaka T, Uchiumi T, Hinoshita E, et al. (1999). "The human multidrug resistance protein 2 gene: functional characterization of the 5'-flanking region and expression in hepatic cells". Hepatology. 30 (6): 1507–12. doi:10.1002/hep.510300617. PMID 10573531. S2CID 22514353.
  • St-Pierre MV, Serrano MA, Macias RI, et al. (2000). "Expression of members of the multidrug resistance protein family in human term placenta". Am. J. Physiol. Regul. Integr. Comp. Physiol. 279 (4): R1495–503. doi:10.1152/ajpregu.2000.279.4.R1495. PMID 11004020. S2CID 36043361.
  • Keitel V, Kartenbeck J, Nies AT, et al. (2001). "Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome". Hepatology. 32 (6): 1317–28. doi:10.1053/jhep.2000.19791. PMID 11093739. S2CID 20920288.
  • Ito S, Ieiri I, Tanabe M, et al. (2001). "Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects". Pharmacogenetics. 11 (2): 175–84. doi:10.1097/00008571-200103000-00008. PMID 11266082.
  • Mor-Cohen R, Zivelin A, Rosenberg N, et al. (2001). "Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome". J. Biol. Chem. 276 (40): 36923–30. doi:10.1074/jbc.M105047200. PMID 11477083.
  • Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P (2005). "Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites". Xenobiotica. 35 (10–11): 1055–66. doi:10.1080/00498250500354493. PMID 16393861. S2CID 6888528.

External links

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