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Multidrug resistance-associated protein 2 - Revision history
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<p><b>New page</b></p><div>{{Infobox_gene}}<br />
'''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]].<ref name="pmid8797578"/><ref name="pmid9284939"/><ref name="entrez"/><br />
<br />
== Function ==<br />
<br />
MRP2 is a member of the superfamily of [[ATP-binding cassette transporter|ATP-binding cassette (ABC) transporters]]. ABC proteins transport various molecules across extra- and intra-[[cellular membrane]]s. 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 [[chemotherapy|anticancer drug]]s such as [[vinblastine]]; therefore, this protein appears to contribute to drug resistance in mammalian cells.<br />
<br />
MRP2 is also expressed in the [[Epithelial polarity#Apical membranes|apical membrane]] of [[proximal renal tubule]] [[endothelial cells]] where they are involved in the excretion of small [[ion|organic anions]].<ref name="pmid16403838">{{cite journal |vauthors=Sekine T, Miyazaki H, Endou H | title = Molecular physiology of renal organic anion transporters | journal = Am. J. Physiol. Renal Physiol. | volume = 290 | issue = 2 | pages = F251–61 |date=February 2006 | pmid = 16403838 | doi = 10.1152/ajprenal.00439.2004 | url = | issn = }}</ref><br />
<br />
== MRP2 inhibitors ==<br />
<br />
{| class="wikitable sortable" border="1"<br />
|-<br />
! Drug<br />
! Class<br />
! Indications<br />
! Source<br />
! Structure<br />
|-<br />
| [[probenecid]]<br />
| [[uricosuric]]<br />
| [[gout]] <br/> [[hyperuricemia]]<br />
| <ref name="pmid10727523"/><br />
| [[image:Probenecid.svg | | |100px]]<br />
|-<br />
| [[furosemide]]<br />
| [[loop diuretic]]<br />
| [[heart failure]] <br/> [[edema]] <br />
| <ref name="pmid10727523"/><br />
| [[image:Furosemide.svg | | |100px]]<br />
|-<br />
| [[ritonavir]]<br />
| [[Protease inhibitor (pharmacology)|protease inhibitor]]<br />
| [[antiretroviral]]<br />
| <ref name="pmid15076241"/> <br />
| [[image:Ritonavir.svg | | |100px]]<br />
|-<br />
| [[saquinavir]]<br />
| [[Protease inhibitor (pharmacology)|protease inhibitor]]<br />
| [[antiretroviral]]<br />
| <ref name="pmid15167283"/><br />
| [[image:Saquinavir.svg | | |100px]]<br />
|-<br />
| [[lamivudine]]<br />
| [[Reverse transcriptase inhibitor#INucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)|Nucleoside analog]]<br />
| [[Antiviral drug|antiviral]]<br />
| <ref name="pmid17172311"/><br />
| [[image:lamivudine.svg | | |100px]]<br />
|-<br />
| [[abacavir]]<br />
| [[Reverse transcriptase inhibitor#INucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)|Nucleoside analog]]<br />
| [[antiretroviral]]<br />
| <ref name="pmid17172311"/><br />
| [[image:Abacavir.svg| | |100px]]<br />
|-<br />
| [[emtricitabine]]<br />
| [[Reverse transcriptase inhibitor#INucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)|Nucleoside analog]]<br />
| [[Antiviral drug|antiviral]]<br />
| <ref name="pmid17172311"/><br />
| [[image:Emtricitabine skeletal.svg | | |100px]]<br />
|-<br />
| [[efavirenz]]<br />
| [[Reverse transcriptase inhibitor#Non-nucleoside reverse transcriptase inhibitors (NNRTIs)|NNRTI]]<br />
| [[antiretroviral]]<br />
| <ref name="pmid17172311"/><br />
| [[image:Efavirenz.svg | | |100px]]<br />
|-<br />
| [[delavirdine]]<br />
| [[Reverse transcriptase inhibitor#Non-nucleoside reverse transcriptase inhibitors (NNRTIs)|NNRTI]]<br />
| [[antiretroviral]]<br />
| <ref name="pmid17172311"/><br />
| [[image:Delavirdine.svg | | |100px]]<br />
|-<br />
| [[nevirapine]]<br />
| [[Reverse transcriptase inhibitor#Non-nucleoside reverse transcriptase inhibitors (NNRTIs)|NNRTI]]<br />
| [[antiretroviral]]<br />
| <ref name="pmid17172311"/><br />
| [[image:Nevirapine.svg | | |100px]]<br />
|-<br />
| [[cidofovir]]<br />
| nucleoside phosphonate<br />
| [[Antiviral drug|antiviral]]<br />
| <ref name="pmid11602668"/> <br />
| [[image:Cidofovir.svg | | |100px]]<br />
|-<br />
| [[adefovir]]<br />
| nucleoside phosphonate<br />
| [[Antiviral drug|antiviral]]<br />
| <ref name="pmid15167283"/><br />
| [[image:Adefovir.svg | | |100px]]<br />
|-<br />
| [[tenofovir]] <br />
| nucleoside phosphonate<br />
| [[Antiviral drug|antiviral]]<br />
| <ref name="pmid17172311"/><br />
| [[image:Tenofovir.svg | | |100px]]<br />
|-<br />
|}<br />
<br />
== Clinical significance ==<br />
=== Dubin-Johnson syndrome ===<br />
<br />
Several different mutations in this gene have been observed in patients with [[Dubin-Johnson syndrome]] (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia.<ref name="entrez"/><ref>{{Cite journal|last=Morii|first=Kazuhiko|last2=Yamamoto|first2=Takeharu|date=2016-07-06|title=Dubin–Johnson Syndrome|url=http://www.nejm.org/doi/10.1056/NEJMicm1509529|journal=New England Journal of Medicine|language=EN|volume=375|issue=1|doi=10.1056/nejmicm1509529|pages=e1|pmid=27406372}}</ref><br />
<br />
=== Iatrogenic Fanconi syndrome ===<br />
<br />
Many negatively charged metabolic waste products are eliminated from the body by the kidneys. These [[organic anion]]s are transported from the blood into the [[endothelial]] cells of the [[proximal convoluted tubule|renal proximal tubules]] by the [[OAT1]] transporter. From there, these waste [[molecules]] are transported into the [[Lumen (anatomy)|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.<br />
<br />
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 [[OAT1#Antiviral induced Fanconi syndrome|iatrogenic Fanconi syndrome]]. The nucleoside phosphonate [[adefovir]] is a MRP2 inhibitor that has been linked to kidney disease.<ref name="pmid12606735"/> [[Tenofovir]]<ref name = "pmid19334329"/> and [[cidofovir]]<ref name = "pmid9257778"/> are also nucleoside phosphonates that inhibit MRP2 and have been associated with Fanconi syndrome.<br />
<br />
==Interactive pathway map==<br />
{{IrinotecanPathway_WP229|highlight=Multidrug_resistance-associated_protein_2}}<br />
<br />
==See also==<br />
* [[ATP-binding cassette transporter]]<br />
<br />
==References==<br />
{{reflist | refs =<br />
<br />
<ref name="pmid8797578">{{cite journal |vauthors=Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, Kagotani K, Okumura K, Akiyama S, Kuwano M | title = A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation | journal = Cancer Res | volume = 56 | issue = 18 | pages = 4124–9 |date=Oct 1996 | pmid = 8797578 | pmc = | doi = | url = http://cancerres.aacrjournals.org/content/56/18/4124.long }}</ref><br />
<br />
<ref name="pmid9284939">{{cite journal |vauthors=van Kuijck MA, Kool M, Merkx GF, Geurts van Kessel A, Bindels RJ, Deen PM, van Os CH | title = Assignment of the canalicular multispecific organic anion transporter gene (CMOAT) to human chromosome 10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization | journal = Cytogenet Cell Genet | volume = 77 | issue = 3–4 | pages = 285–7 |date=Sep 1997 | pmid = 9284939 | pmc = | doi =10.1159/000134599 }}</ref><br />
<br />
<ref name="entrez">{{cite web | title = Entrez Gene: ABCC2 ATP-binding cassette, sub-family C (CFTR/MRP), member 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1244| accessdate = }}</ref><br />
<br />
<ref name="pmid12606735">{{cite journal |vauthors=Marcellin P, Chang TT, Lim SG, etal |title=Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B |journal=N. Engl. J. Med. |volume=348 |issue=9 |pages=808–16 |date=February 2003 |pmid=12606735 |doi=10.1056/NEJMoa020681 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12606735&promo=ONFLNS19}}</ref><br />
<br />
<ref name="pmid17172311">{{cite journal |vauthors=Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE | title = Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors | journal = [[Drug Metab. Dispos.]] | volume = 35 | issue = 3 | pages = 340–4 |date=March 2007 | doi = 10.1124/dmd.106.012765 | pmid = 17172311 | issn = }}</ref><br />
<br />
<ref name = "pmid19334329">{{cite journal |vauthors=Atta MG, Fine DM | title = Editorial comment: tenofovir nephrotoxicity--the disconnect between clinical trials and real-world practice | journal = AIDS Read | volume = 19 | issue = 3 | pages = 118–9 |date=March 2009 | pmid = 19334329 | doi = | url = | issn = }}</ref><br />
<br />
<ref name = "pmid9257778">{{cite journal |vauthors=Vittecoq D, Dumitrescu L, Beaufils H, Deray G | title = Fanconi syndrome associated with cidofovir therapy | journal = Antimicrob. Agents Chemother. | volume = 41 | issue = 8 | pages = 1846 |date=August 1997 | pmid = 9257778 | pmc = 164022 | doi = | url = | issn = }}</ref><br />
<br />
<ref name="pmid15076241">{{cite journal<br />
|vauthors=Peyrière H, Reynes J, Rouanet I, etal | title = Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases<br />
| journal = [[J. Acquir. Immune Defic. Syndr.]]<br />
| volume = 35<br />
| issue = 3<br />
| pages = 269–73<br />
|date=March 2004<br />
| pmid = 15076241<br />
| doi = <br />
| url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=35&issue=3&spage=269<br />
| issn = <br />
}}</ref><br />
<br />
<ref name="pmid15167283">{{cite journal<br />
|vauthors=Gimenez F, Fernandez C, Mabondzo A | title = Transport of HIV protease inhibitors through the blood–brain barrier and interactions with the efflux proteins, P-glycoprotein and multidrug resistance proteins<br />
| journal = [[J. Acquir. Immune Defic. Syndr.]]<br />
| volume = 36<br />
| issue = 2<br />
| pages = 649–58<br />
|date=June 2004<br />
| pmid = 15167283<br />
| doi = 10.1097/00126334-200406010-00001<br />
| url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=36&issue=2&spage=649<br />
| issn = <br />
}}</ref><br />
<br />
<ref name="pmid11602668">{{cite journal<br />
| author = Miller DS<br />
| title = Nucleoside phosphonate interactions with multiple organic anion transporters in renal proximal tubule<br />
| journal = [[J. Pharmacol. Exp. Ther.]]<br />
| volume = 299<br />
| issue = 2<br />
| pages = 567–74<br />
|date=November 2001<br />
| pmid = 11602668<br />
| doi = <br />
| url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11602668<br />
| issn = <br />
}}</ref><br />
<br />
<ref name="pmid10727523">{{cite journal<br />
|vauthors=Bakos E, Evers R, Sinkó E, Váradi A, Borst P, Sarkadi B | title = Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions<br />
| journal = [[Mol. Pharmacol.]]<br />
| volume = 57<br />
| issue = 4<br />
| pages = 760–8<br />
|date=April 2000<br />
| pmid = 10727523<br />
| doi = <br />
| url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10727523<br />
| issn = <br />
}}</ref><br />
<br />
}}<br />
<br />
==Further reading==<br />
{{refbegin | 2}}<br />
{{PBB_Further_reading <br />
| citations = <br />
*{{cite journal |vauthors=Keppler D, König J |title=Hepatic secretion of conjugated drugs and endogenous substances. |journal=Semin. Liver Dis. |volume=20 |issue= 3 |pages= 265–72 |year= 2001 |pmid= 11076395 |doi=10.1055/s-2000-9391 }}<br />
*{{cite journal |vauthors=Gerk PM, Vore M |title=Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. |journal=J. Pharmacol. Exp. Ther. |volume=302 |issue= 2 |pages= 407–15 |year= 2002 |pmid= 12130697 |doi= 10.1124/jpet.102.035014 }}<br />
*{{cite journal |vauthors=Mayer R, Kartenbeck J, Büchler M, etal |title=Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes. |journal=J. Cell Biol. |volume=131 |issue= 1 |pages= 137–50 |year= 1995 |pmid= 7559771 |doi=10.1083/jcb.131.1.137 | pmc=2120605 }}<br />
*{{cite journal |vauthors=Büchler M, König J, Brom M, etal |title=cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. |journal=J. Biol. Chem. |volume=271 |issue= 25 |pages= 15091–8 |year= 1996 |pmid= 8662992 |doi=10.1074/jbc.271.25.15091 }}<br />
*{{cite journal |vauthors=Paulusma CC, Kool M, Bosma PJ, etal |title=A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. |journal=Hepatology |volume=25 |issue= 6 |pages= 1539–42 |year= 1997 |pmid= 9185779 |doi= 10.1002/hep.510250635 }}<br />
*{{cite journal |vauthors=Wada M, Toh S, Taniguchi K, etal |title=Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. |journal=Hum. Mol. Genet. |volume=7 |issue= 2 |pages= 203–7 |year= 1998 |pmid= 9425227 |doi=10.1093/hmg/7.2.203 }}<br />
*{{cite journal |vauthors=Evers R, Kool M, van Deemter L, etal |title=Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. |journal=J. Clin. Invest. |volume=101 |issue= 7 |pages= 1310–9 |year= 1998 |pmid= 9525973 |doi=10.1172/JCI119886 | pmc=508708 }}<br />
*{{cite journal |vauthors=Kajihara S, Hisatomi A, Mizuta T, etal |title=A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome. |journal=Biochem. Biophys. Res. Commun. |volume=253 |issue= 2 |pages= 454–7 |year= 1999 |pmid= 9878557 |doi= 10.1006/bbrc.1998.9780 }}<br />
*{{cite journal |vauthors=Toh S, Wada M, Uchiumi T, etal |title=Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. |journal=Am. J. Hum. Genet. |volume=64 |issue= 3 |pages= 739–46 |year= 1999 |pmid= 10053008 |doi=10.1086/302292 | pmc=1377791 }}<br />
*{{cite journal |vauthors=Schaub TP, Kartenbeck J, König J, etal |title=Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. |journal=J. Am. Soc. Nephrol. |volume=10 |issue= 6 |pages= 1159–69 |year= 1999 |pmid= 10361853 |doi= }}<br />
*{{cite journal |vauthors=Tsujii H, König J, Rost D, etal |title=Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. |journal=Gastroenterology |volume=117 |issue= 3 |pages= 653–60 |year= 1999 |pmid= 10464142 |doi=10.1016/S0016-5085(99)70459-2 }}<br />
*{{cite journal |vauthors=Kocher O, Comella N, Gilchrist A, etal |title=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. |journal=Lab. Invest. |volume=79 |issue= 9 |pages= 1161–70 |year= 1999 |pmid= 10496535 |doi= }}<br />
*{{cite journal |vauthors=Tanaka T, Uchiumi T, Hinoshita E, etal |title=The human multidrug resistance protein 2 gene: functional characterization of the 5'-flanking region and expression in hepatic cells. |journal=Hepatology |volume=30 |issue= 6 |pages= 1507–12 |year= 1999 |pmid= 10573531 |doi= 10.1002/hep.510300617 }}<br />
*{{cite journal |vauthors=St-Pierre MV, Serrano MA, Macias RI, etal |title=Expression of members of the multidrug resistance protein family in human term placenta. |journal=Am. J. Physiol. Regul. Integr. Comp. Physiol. |volume=279 |issue= 4 |pages= R1495–503 |year= 2000 |pmid= 11004020 |doi= }}<br />
*{{cite journal |vauthors=Keitel V, Kartenbeck J, Nies AT, etal |title=Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. |journal=Hepatology |volume=32 |issue= 6 |pages= 1317–28 |year= 2001 |pmid= 11093739 |doi= 10.1053/jhep.2000.19791 }}<br />
*{{cite journal |vauthors=Ito S, Ieiri I, Tanabe M, etal |title=Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. |journal=Pharmacogenetics |volume=11 |issue= 2 |pages= 175–84 |year= 2001 |pmid= 11266082 |doi=10.1097/00008571-200103000-00008 }}<br />
*{{cite journal |vauthors=Mor-Cohen R, Zivelin A, Rosenberg N, etal |title=Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. |journal=J. Biol. Chem. |volume=276 |issue= 40 |pages= 36923–30 |year= 2001 |pmid= 11477083 |doi= 10.1074/jbc.M105047200 }}<br />
}}<br />
*{{cite journal<br />
|vauthors=Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P | title = Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites<br />
| journal = [[Xenobiotica]]<br />
| volume = 35<br />
| issue = 10–11<br />
| pages = 1055–66<br />
| year = 2005<br />
| pmid = 16393861<br />
| doi = 10.1080/00498250500354493 <br />
| url = http://informahealthcare.com/doi/abs/10.1080/00498250500354493%20<br />
| issn = <br />
}}<br />
{{refend}}<br />
<br />
== External links ==<br />
* {{MeshName|ABCC2+protein,+human}}<br />
<br />
{{NLM content}}<br />
{{ABC transporters}}<br />
<br />
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --><br />
{{PBB_Controls<br />
| update_page = yes <br />
| require_manual_inspection = no <br />
| update_protein_box = yes<br />
| update_summary = yes<br />
| update_citations = no<br />
}}<br />
<br />
{{DEFAULTSORT:Abcc2}}<br />
[[Category:ABC transporters]]</div>
en>KolbertBot