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{{PBB|geneid=1244}}
{{Short description|Protein found in humans}}
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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]].<ref name="pmid8797578"/><ref name="pmid9284939"/><ref name="entrez"/>
{{Infobox_gene}}
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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]].<ref name="pmid8797578"/><ref name="pmid9284939"/><ref name="entrez"/>


== Function ==
== Function ==


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.
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.


MRP2 is also expressed in on 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 | author = 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 | year = 2006 | month = February | pmid = 16403838 | doi = 10.1152/ajprenal.00439.2004 | url = | issn = }}</ref>
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 }}</ref>


== MRP2 inhibitors ==
== MRP2 inhibitors ==
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| [[gout]] <br/> [[hyperuricemia]]
| [[gout]] <br/> [[hyperuricemia]]
| <ref name="pmid10727523"/>
| <ref name="pmid10727523"/>
| [[image:Probenecid.svg | | |100px]]
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| [[furosemide]]
| [[furosemide]]
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| [[heart failure]] <br/> [[edema]]
| [[heart failure]] <br/> [[edema]]
| <ref name="pmid10727523"/>
| <ref name="pmid10727523"/>
| [[image:Furosemide.svg | | |100px]]
| [[image:Furosemide.svg|100px]]
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| [[ritonavir]]
| [[ritonavir]]
| [[protease inhibitor]]
| [[Protease inhibitor (pharmacology)|protease inhibitor]]
| [[antiretroviral]]
| [[antiretroviral]]
| <ref name="pmid15076241"/>
| <ref name="pmid15076241"/>
| [[image:Ritonavir.svg | | |100px]]
| [[image:Ritonavir.svg|100px]]
|-
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| [[saquinavir]]
| [[saquinavir]]
| [[protease inhibitor]]
| [[Protease inhibitor (pharmacology)|protease inhibitor]]
| [[antiretroviral]]
| [[antiretroviral]]
| <ref name="pmid15167283"/>
| <ref name="pmid15167283"/>
| [[image:Saquinavir.svg | | |100px]]
| [[image:Saquinavir structure.svg|100px]]
|-
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| [[lamivudine]]
| [[lamivudine]]
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| [[Antiviral drug|antiviral]]
| [[Antiviral drug|antiviral]]
| <ref name="pmid17172311"/>
| <ref name="pmid17172311"/>
| [[image:lamivudine.svg | | |100px]]
| [[image:lamivudine.svg|100px]]
|-
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| [[abacavir]]
| [[abacavir]]
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| [[antiretroviral]]
| [[antiretroviral]]
| <ref name="pmid17172311"/>
| <ref name="pmid17172311"/>
| [[image:Abacavir.png | | |100px]]
| [[image:Abacavir.svg|100px]]
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| [[emtricitabine]]
| [[emtricitabine]]
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| [[Antiviral drug|antiviral]]
| [[Antiviral drug|antiviral]]
| <ref name="pmid17172311"/>
| <ref name="pmid17172311"/>
| [[image:Emtricitabine skeletal.svg | | |100px]]
| [[image:Emtricitabine skeletal.svg|100px]]
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| [[efavirenz]]
| [[efavirenz]]
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| [[antiretroviral]]
| [[antiretroviral]]
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| [[delavirdine]]
| [[delavirdine]]
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| [[antiretroviral]]
| [[antiretroviral]]
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| [[nevirapine]]
| [[nevirapine]]
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| [[antiretroviral]]
| [[antiretroviral]]
| <ref name="pmid17172311"/>
| <ref name="pmid17172311"/>
| [[image:Nevirapine.svg | | |100px]]
| [[image:Nevirapine.svg|100px]]
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| [[cidofovir]]
| [[cidofovir]]
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| [[Antiviral drug|antiviral]]
| [[Antiviral drug|antiviral]]
| <ref name="pmid11602668"/>
| <ref name="pmid11602668"/>
| [[image:Cidofovir.svg | | |100px]]
| [[image:Cidofovir.svg|100px]]
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| [[adefovir]]
| [[adefovir]]
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| [[Antiviral drug|antiviral]]
| [[Antiviral drug|antiviral]]
| <ref name="pmid15167283"/>
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| [[image:Adefovir.svg | | |100px]]
| [[image:Adefovir.svg|100px]]
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| [[tenofovir]]
| [[tenofovir]]
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| [[Antiviral drug|antiviral]]
| [[Antiviral drug|antiviral]]
| <ref name="pmid17172311"/>
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| [[image:Tenofovir.svg | | |100px]]
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== Clinical significance ==
== Clinical significance ==
=== Dubin-Johnson syndrome ===
=== 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.<ref name="entrez"/>
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|last1=Morii|first1=Kazuhiko|last2=Yamamoto|first2=Takeharu|date=2016-07-06|title=Dubin–Johnson Syndrome|journal=New England Journal of Medicine|language=EN|volume=375|issue=1|doi=10.1056/nejmicm1509529|pages=e1|pmid=27406372}}</ref>


=== Iatrogenic Fanconi syndrome ===
=== Iatrogenic Fanconi syndrome ===


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 build up of organic anions in the [[cytoplasm]] of the cells.
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.


Drugs that inhibit the MRP2 transporter can cause a build up 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.
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.<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.


==Interactive pathway map==
==Interactive pathway map==
{{IrinotecanPathway_WP229|highlight=ABCC2}}
{{IrinotecanPathway_WP229|highlight=Multidrug_resistance-associated_protein_2}}


==See also==
==See also==
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==References==
==References==
{{reflist | refs =
{{reflist | refs =


<ref name="pmid8797578">{{cite journal | author = 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 | year = 1996 | month = Oct | pmid = 8797578 | pmc = | doi = | url = http://cancerres.aacrjournals.org/content/56/18/4124.long }}</ref>
<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 | url = http://cancerres.aacrjournals.org/content/56/18/4124.long }}</ref>


<ref name="pmid9284939">{{cite journal | author = 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 | year = 1997 | month = Sep | pmid = 9284939 | pmc = | doi =10.1159/000134599 }}</ref>
<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 | doi =10.1159/000134599 | s2cid = 46739365 }}</ref>


<ref name="entrez">{{cite web | title = Entrez Gene: ABCC2 ATP-binding cassette, sub-family C (CFTR/MRP), member 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1244| accessdate = }}</ref>
<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}}</ref>


<ref name="pmid12606735">{{cite journal |author=Marcellin P, Chang TT, Lim SG, ''et al.'' |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 |year=2003 |month=February |pmid=12606735 |doi=10.1056/NEJMoa020681 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12606735&promo=ONFLNS19}}</ref>
<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=https://scholarscompass.vcu.edu/intmed_pubs/45 |doi-access=free }}</ref>


<ref name="pmid17172311">{{cite journal | author = 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 | year = 2007 | month = March | doi = 10.1124/dmd.106.012765 | pmid = 17172311 | issn = }}</ref>
<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 | s2cid = 46141353 }}</ref>


<ref name = "pmid19334329">{{cite journal | author = 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 | year = 2009 | month = March | pmid = 19334329 | doi = | url = | issn = }}</ref>
<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 }}</ref>


<ref name = "pmid9257778">{{cite journal | author = 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 | year = 1997 | month = August | pmid = 9257778 | pmc = 164022 | doi = | url = | issn = }}</ref>
<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 = 10.1128/AAC.41.8.1846}}</ref>


<ref name="pmid15076241">{{cite journal
<ref name="pmid15076241">{{cite journal
| author = Peyrière H, Reynes J, Rouanet I, ''et al.''
|vauthors=Peyrière H, Reynes J, Rouanet I, etal | title = Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases
| title = Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases
| journal = [[J. Acquir. Immune Defic. Syndr.]]
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| url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=35&issue=3&spage=269
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}}</ref>
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}}</ref>


<ref name="pmid15167283">{{cite journal
<ref name="pmid15167283">{{cite journal
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|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
| author = Gimenez F, Fernandez C, Mabondzo A
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| title = Transport of HIV protease inhibitors through the blood-brain barrier and interactions with the efflux proteins, P-glycoprotein and multidrug resistance proteins
| journal = [[J. Acquir. Immune Defic. Syndr.]]
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| issn =
| doi-access = free
}}</ref>
}}</ref>


<ref name="pmid11602668">{{cite journal
<ref name="pmid11602668">{{cite journal
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| issue = 2
| issue = 2
| pages = 567–74
| pages = 567–74
| year = 2001
|date=November 2001
| month = November
| pmid = 11602668
| pmid = 11602668
| doi =
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| url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11602668
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| issn =
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<ref name="pmid10727523">{{cite journal
<ref name="pmid10727523">{{cite journal
| author = Bakos E, Evers R, Sinkó E, Váradi A, Borst P, Sarkadi B
|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
| title = Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions
| journal = [[Mol. Pharmacol.]]
| journal = [[Mol. Pharmacol.]]
| volume = 57
| volume = 57
| issue = 4
| issue = 4
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==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
*{{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 |s2cid=25626705 }}
{{PBB_Further_reading
*{{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 |s2cid=873234 }}
| citations =
*{{cite journal | author=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 }}
*{{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 }}
*{{cite journal | author=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 }}
*{{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 |doi-access=free }}
*{{cite journal | author=Mayer R, Kartenbeck J, Büchler M, ''et al.'' |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 }}
*{{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 |s2cid=22635775 |url=https://pure.uva.nl/ws/files/3040383/3291_30375y.pdf |doi-access=free }}
*{{cite journal | author=Büchler M, König J, Brom M, ''et al.'' |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 }}
*{{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 |doi-access=free }}
*{{cite journal | author=Paulusma CC, Kool M, Bosma PJ, ''et al.'' |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 }}
*{{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 }}
*{{cite journal | author=Wada M, Toh S, Taniguchi K, ''et al.'' |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 }}
*{{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 }}
*{{cite journal | author=Evers R, Kool M, van Deemter L, ''et al.'' |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 }}
*{{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 }}
*{{cite journal | author=Kajihara S, Hisatomi A, Mizuta T, ''et al.'' |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 }}
*{{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 |doi=10.1681/ASN.V1061159 |pmid= 10361853 |doi-access=free }}
*{{cite journal | author=Toh S, Wada M, Uchiumi T, ''et al.'' |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 }}
*{{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 }}
*{{cite journal | author=Schaub TP, Kartenbeck J, König J, ''et al.'' |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= }}
*{{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 }}
*{{cite journal | author=Tsujii H, König J, Rost D, ''et al.'' |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 }}
*{{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 |s2cid=22514353 |doi-access=free }}
*{{cite journal | author=Kocher O, Comella N, Gilchrist A, ''et al.'' |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= }}
*{{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= 10.1152/ajpregu.2000.279.4.R1495|s2cid=36043361 }}
*{{cite journal | author=Tanaka T, Uchiumi T, Hinoshita E, ''et al.'' |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 }}
*{{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 |s2cid=20920288 |doi-access=free }}
*{{cite journal | author=St-Pierre MV, Serrano MA, Macias RI, ''et al.'' |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= }}
*{{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 }}
*{{cite journal | author=Keitel V, Kartenbeck J, Nies AT, ''et al.'' |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 }}
*{{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 |doi-access= free }}
*{{cite journal | author=Ito S, Ieiri I, Tanabe M, ''et al.'' |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 }}
*{{cite journal | author=Mor-Cohen R, Zivelin A, Rosenberg N, ''et al.'' |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 }}
}}
*{{cite journal
*{{cite journal
| author = Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P
|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
| title = Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites
| journal = [[Xenobiotica]]
| journal = [[Xenobiotica]]
| volume = 35
| volume = 35
| issue = 10-11
| issue = 10–11
| pages = 1055–66
| pages = 1055–66
| year = 2005
| year = 2005
| pmid = 16393861
| pmid = 16393861
| doi = 10.1080/00498250500354493
| doi = 10.1080/00498250500354493
| s2cid = 6888528
| url = http://informahealthcare.com/doi/abs/10.1080/00498250500354493%20
| issn =
}}
}}
{{refend}}
{{refend}}
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{{ABC transporters}}
{{ABC transporters}}


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{{DEFAULTSORT:Abcc2}}
{{DEFAULTSORT:Abcc2}}
[[Category:ABC transporters]]
[[Category:ATP-binding cassette transporters]]


{{membrane-protein-stub}}

Latest revision as of 18:12, 10 June 2024

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

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

[edit]

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

[edit]

Dubin–Johnson syndrome

[edit]

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

[edit]

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

[edit]

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

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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
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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

[edit]

References

[edit]
  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

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[edit]

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

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