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Literature summary extracted from

  • Russel, F.G.; Koenderink, J.B.; Masereeuw, R.
    Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules (2008), Trends Pharmacol. Sci., 29, 200-207.
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
7.6.2.2 glutathione required for transport of leukotriene B4 Homo sapiens
7.6.2.2 additional information elevated levels of hepatic MRP4 are found after hepatotoxicant exposure, probably mediated via transcription factor NFE2-related factor 2. Human cells upregulate MRP4 after long-term exposure to nucleoside-based drugs Homo sapiens

Application

EC Number Application Comment Organism
7.6.2.2 diagnostics in patients with neuroblastoma, increased MRP4 expression has prognostic value Homo sapiens
7.6.2.2 drug development MRP4 is a potential target for drug development, e.g. in the treatment of hyperuricaemia Homo sapiens
7.6.2.2 medicine specific inhibitors of MRP4 can be a valuable asset for enhancing the brain penetration and therapeutic efficacy of adefovir and tenofovir Homo sapiens

Cloned(Commentary)

EC Number Cloned (Comment) Organism
7.6.2.2 gene MRP4, located on chromosome 13q32.1 Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
7.6.2.2 additional information construction of a Mrp4-knockout mouse model with cell-type specific expression and subcellular localisation, overview Mus musculus

Inhibitors

EC Number Inhibitors Comment Organism Structure
7.6.2.2 4-(2-aminoethyl)benzenesulfonylfluoride
-
Homo sapiens
7.6.2.2 celecoxib
-
Homo sapiens
7.6.2.2 dipyridamole potent inhibition of MRP4 Homo sapiens
7.6.2.2 indomethacin
-
Homo sapiens
7.6.2.2 losartan
-
Homo sapiens
7.6.2.2 MK571
-
Homo sapiens
7.6.2.2 probenecid
-
Homo sapiens
7.6.2.2 quercetin
-
Homo sapiens
7.6.2.2 sildenafil potent inhibition of MRP4 Homo sapiens
7.6.2.2 sulindac
-
Homo sapiens

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
7.6.2.2 additional information
-
additional information substrate specificity, overview Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
7.6.2.2 membrane
-
Mus musculus 16020
-
7.6.2.2 membrane MRP4 shows a dual membrane localisation in polarised cell types Homo sapiens 16020
-
7.6.2.2 plasma membrane
-
Homo sapiens 5886
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
7.6.2.2 ATP + H2O + 17beta-estradiol 17-(beta-D-glucuronide)/in Homo sapiens
-
ADP + phosphate + 17beta-estradiol 17-(beta-D-glucuronide)/out
-
?
7.6.2.2 ATP + H2O + 4-(2-aminoethyl)benzenesulfonylfluoride/in Homo sapiens
-
ADP + phosphate + 4-(2-aminoethyl)benzenesulfonylfluoride/out
-
?
7.6.2.2 ATP + H2O + 4-aminohippuric acid/in Homo sapiens
-
ADP + phosphate + 4-aminohippuric acid/out
-
?
7.6.2.2 ATP + H2O + adefovir/in Homo sapiens
-
ADP + phosphate + adefovir/out
-
?
7.6.2.2 ATP + H2O + allopurinol/in Homo sapiens
-
ADP + phosphate + allopurinol/out
-
?
7.6.2.2 ATP + H2O + cAMP/in Homo sapiens
-
ADP + phosphate + cAMP/out
-
?
7.6.2.2 ATP + H2O + cefazolin/in Homo sapiens
-
ADP + phosphate + cefazolin/out
-
?
7.6.2.2 ATP + H2O + cefmetazole/in Homo sapiens
-
ADP + phosphate + cefmetazole/out
-
?
7.6.2.2 ATP + H2O + cefotaxime/in Homo sapiens
-
ADP + phosphate + cefotaxime/out
-
?
7.6.2.2 ATP + H2O + ceftizoxime/in Homo sapiens
-
ADP + phosphate + ceftizoxime/out
-
?
7.6.2.2 ATP + H2O + celecoxib/in Homo sapiens
-
ADP + phosphate + celecoxib/out
-
?
7.6.2.2 ATP + H2O + cGMP/in Homo sapiens
-
ADP + phosphate + cGMP/out
-
?
7.6.2.2 ATP + H2O + chenodeoxycholylglycine/in Homo sapiens
-
ADP + phosphate + chenodeoxycholylglycine/out
-
?
7.6.2.2 ATP + H2O + chenodeoxycholyltaurine/in Homo sapiens
-
ADP + phosphate + chenodeoxycholyltaurine/out
-
?
7.6.2.2 ATP + H2O + cholate/in Homo sapiens
-
ADP + phosphate + cholate/out
-
?
7.6.2.2 ATP + H2O + cholylglycine/in Homo sapiens
-
ADP + phosphate + cholylglycine/out
-
?
7.6.2.2 ATP + H2O + cholytaurine/in Homo sapiens
-
ADP + phosphate + cholytaurine/out
-
?
7.6.2.2 ATP + H2O + dehydroepiandrosterone sulfate/in Homo sapiens
-
ADP + phosphate + dehydroepiandrosterone sulfate/out
-
?
7.6.2.2 ATP + H2O + deoxycholylglycine/in Homo sapiens
-
ADP + phosphate + deoxycholylglycine/out
-
?
7.6.2.2 ATP + H2O + dipyridamole/in Homo sapiens
-
ADP + phosphate + dipyridamole/out
-
?
7.6.2.2 ATP + H2O + edaravone glucuronide/in Homo sapiens
-
ADP + phosphate + edaravone glucuronide/out
-
?
7.6.2.2 ATP + H2O + furosemide/in Homo sapiens
-
ADP + phosphate + furosemide/out
-
?
7.6.2.2 ATP + H2O + hydrochlorothiazide/in Homo sapiens
-
ADP + phosphate + hydrochlorothiazide/out
-
?
7.6.2.2 ATP + H2O + indomethacin/in Homo sapiens
-
ADP + phosphate + indomethacin/out
-
?
7.6.2.2 ATP + H2O + leucovorin/in Homo sapiens
-
ADP + phosphate + leucovorin/out
-
?
7.6.2.2 ATP + H2O + leukotriene B4/in Homo sapiens MRP4 only transports leukotriene B4 in the presence of glutathione ADP + phosphate + leukotriene B4/out
-
?
7.6.2.2 ATP + H2O + leukotriene C4/in Homo sapiens glutathione is not required ADP + phosphate + leukotriene C4/out
-
?
7.6.2.2 ATP + H2O + methotrexate/in Homo sapiens
-
ADP + phosphate + methotrexate/out
-
?
7.6.2.2 ATP + H2O + olmesartan/in Homo sapiens
-
ADP + phosphate + olmesartan/out
-
?
7.6.2.2 ATP + H2O + probenecid/in Homo sapiens
-
ADP + phosphate + probenecid/out
-
?
7.6.2.2 ATP + H2O + prostaglandin E1/in Homo sapiens
-
ADP + phosphate + prostaglandin E1/out
-
?
7.6.2.2 ATP + H2O + prostaglandin E2/in Homo sapiens
-
ADP + phosphate + prostaglandin E2/out
-
?
7.6.2.2 ATP + H2O + prostaglandin F2alpha/in Homo sapiens
-
ADP + phosphate + prostaglandin F2alpha/out
-
?
7.6.2.2 ATP + H2O + taurocholate/in Homo sapiens
-
ADP + phosphate + taurocholate/out
-
?
7.6.2.2 ATP + H2O + tenofovir/in Homo sapiens
-
ADP + phosphate + tenofovir/out
-
?
7.6.2.2 ATP + H2O + thromboxane B2/in Homo sapiens
-
ADP + phosphate + thromboxane B2/out
-
?
7.6.2.2 ATP + H2O + topotecan/in Homo sapiens
-
ADP + phosphate + topotecan/out
-
?
7.6.2.2 ATP + H2O + urate/in Homo sapiens MRP4 is the first secretory transporter identified in the bidirectional renal handling of urate and could be a potential drug target in the treatment of hyperuricaemia, regulation, overview ADP + phosphate + urate/out
-
?
7.6.2.2 ATP + H2O + ursodeoxycholylglycine/in Homo sapiens
-
ADP + phosphate + ursodeoxycholylglycine/out
-
?
7.6.2.2 ATP + H2O + ursodeoxycholyltaurine/in Homo sapiens
-
ADP + phosphate + ursodeoxycholyltaurine/out
-
?
7.6.2.2 ATP + H2O + xenobiotic/in Mus musculus in the brain, MRP4 limits the entry of drugs and is involved in nociception, probably as a result of reduced plasma prostaglandins. In the kidney, MRP4 mediates the active tubular secretion of diuretics, antiviral nucleosides and cephalosporins. In the liver, MRP4 mediates the efflux of bile acid to the blood, and knockout mice are more sensitive to cholestatic-induced liver injury. MRP4 protects bone marrow cells and the gastrointestinal tract against cytotoxic drugs and appears to be involved in secretory diarrhoea via coupling with CFTR ADP + phosphate + xenobiotic/out
-
?
7.6.2.2 ATP + H2O + xenobiotic/in Homo sapiens MRP4 limits brain entry and promotes renal excretion of drugs. In addition to its role in the body distribution and renal excretion of a wide variety of antiviral, cytostatic, antibiotic and cardiovascular drugs, MRP4/ABCC4 has the ability to transport molecules involved in cellular signalling. These molecules include cyclic nucleotides, eicosanoids, urate and conjugated steroids. The unique structure, regulation and dual localisation of MRP4 in polarised cells could be connected with a key function in cellular protection and extracellular signalling pathways, overview ADP + phosphate + xenobiotic/out
-
?
7.6.2.2 additional information Homo sapiens substrate specificity, overview. Renal excretion is an important route of elimination for many MRP4 substrates. MRP4 has a putative pathophysiological function in signalling, and it protects the liver from accumulation of toxic bile acids during cholestasis by facilitating their efflux into blood for ultimate renal excretion ?
-
?

Organism

EC Number Organism UniProt Comment Textmining
7.6.2.2 Homo sapiens
-
-
-
7.6.2.2 Mus musculus
-
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
7.6.2.2 blood platelet dense granules Homo sapiens
-
7.6.2.2 brain MRP4 is mainly expressed in the luminal membrane of capillary endothelium, but also in the basolateral membrane of choroid plexus and in astrocytes Homo sapiens
-
7.6.2.2 kidney localisation of MRP4 to the apical membrane of kidney proximal tubules Homo sapiens
-
7.6.2.2 liver MRP4 expression is highly variable and is transcriptionally regulated through the constitutive androstane receptor Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
7.6.2.2 ATP + H2O + 17beta-estradiol 17-(beta-D-glucuronide)/in
-
Homo sapiens ADP + phosphate + 17beta-estradiol 17-(beta-D-glucuronide)/out
-
?
7.6.2.2 ATP + H2O + 4-(2-aminoethyl)benzenesulfonylfluoride/in
-
Homo sapiens ADP + phosphate + 4-(2-aminoethyl)benzenesulfonylfluoride/out
-
?
7.6.2.2 ATP + H2O + 4-aminohippuric acid/in
-
Homo sapiens ADP + phosphate + 4-aminohippuric acid/out
-
?
7.6.2.2 ATP + H2O + adefovir/in
-
Homo sapiens ADP + phosphate + adefovir/out
-
?
7.6.2.2 ATP + H2O + allopurinol/in
-
Homo sapiens ADP + phosphate + allopurinol/out
-
?
7.6.2.2 ATP + H2O + cAMP/in
-
Homo sapiens ADP + phosphate + cAMP/out
-
?
7.6.2.2 ATP + H2O + cefazolin/in
-
Homo sapiens ADP + phosphate + cefazolin/out
-
?
7.6.2.2 ATP + H2O + cefmetazole/in
-
Homo sapiens ADP + phosphate + cefmetazole/out
-
?
7.6.2.2 ATP + H2O + cefotaxime/in
-
Homo sapiens ADP + phosphate + cefotaxime/out
-
?
7.6.2.2 ATP + H2O + ceftizoxime/in
-
Homo sapiens ADP + phosphate + ceftizoxime/out
-
?
7.6.2.2 ATP + H2O + celecoxib/in
-
Homo sapiens ADP + phosphate + celecoxib/out
-
?
7.6.2.2 ATP + H2O + cGMP/in
-
Homo sapiens ADP + phosphate + cGMP/out
-
?
7.6.2.2 ATP + H2O + chenodeoxycholylglycine/in
-
Homo sapiens ADP + phosphate + chenodeoxycholylglycine/out
-
?
7.6.2.2 ATP + H2O + chenodeoxycholyltaurine/in
-
Homo sapiens ADP + phosphate + chenodeoxycholyltaurine/out
-
?
7.6.2.2 ATP + H2O + cholate/in
-
Homo sapiens ADP + phosphate + cholate/out
-
?
7.6.2.2 ATP + H2O + cholylglycine/in
-
Homo sapiens ADP + phosphate + cholylglycine/out
-
?
7.6.2.2 ATP + H2O + cholytaurine/in
-
Homo sapiens ADP + phosphate + cholytaurine/out
-
?
7.6.2.2 ATP + H2O + dehydroepiandrosterone sulfate/in
-
Homo sapiens ADP + phosphate + dehydroepiandrosterone sulfate/out
-
?
7.6.2.2 ATP + H2O + deoxycholylglycine/in
-
Homo sapiens ADP + phosphate + deoxycholylglycine/out
-
?
7.6.2.2 ATP + H2O + dipyridamole/in
-
Homo sapiens ADP + phosphate + dipyridamole/out
-
?
7.6.2.2 ATP + H2O + edaravone glucuronide/in
-
Homo sapiens ADP + phosphate + edaravone glucuronide/out
-
?
7.6.2.2 ATP + H2O + furosemide/in
-
Homo sapiens ADP + phosphate + furosemide/out
-
?
7.6.2.2 ATP + H2O + hydrochlorothiazide/in
-
Homo sapiens ADP + phosphate + hydrochlorothiazide/out
-
?
7.6.2.2 ATP + H2O + indomethacin/in
-
Homo sapiens ADP + phosphate + indomethacin/out
-
?
7.6.2.2 ATP + H2O + leucovorin/in
-
Homo sapiens ADP + phosphate + leucovorin/out
-
?
7.6.2.2 ATP + H2O + leukotriene B4/in MRP4 only transports leukotriene B4 in the presence of glutathione Homo sapiens ADP + phosphate + leukotriene B4/out
-
?
7.6.2.2 ATP + H2O + leukotriene C4/in glutathione is not required Homo sapiens ADP + phosphate + leukotriene C4/out
-
?
7.6.2.2 ATP + H2O + methotrexate/in
-
Homo sapiens ADP + phosphate + methotrexate/out
-
?
7.6.2.2 ATP + H2O + olmesartan/in
-
Homo sapiens ADP + phosphate + olmesartan/out
-
?
7.6.2.2 ATP + H2O + probenecid/in
-
Homo sapiens ADP + phosphate + probenecid/out
-
?
7.6.2.2 ATP + H2O + prostaglandin E1/in
-
Homo sapiens ADP + phosphate + prostaglandin E1/out
-
?
7.6.2.2 ATP + H2O + prostaglandin E2/in
-
Homo sapiens ADP + phosphate + prostaglandin E2/out
-
?
7.6.2.2 ATP + H2O + prostaglandin F2alpha/in
-
Homo sapiens ADP + phosphate + prostaglandin F2alpha/out
-
?
7.6.2.2 ATP + H2O + taurocholate/in
-
Homo sapiens ADP + phosphate + taurocholate/out
-
?
7.6.2.2 ATP + H2O + tenofovir/in
-
Homo sapiens ADP + phosphate + tenofovir/out
-
?
7.6.2.2 ATP + H2O + thromboxane B2/in
-
Homo sapiens ADP + phosphate + thromboxane B2/out
-
?
7.6.2.2 ATP + H2O + topotecan/in
-
Homo sapiens ADP + phosphate + topotecan/out
-
?
7.6.2.2 ATP + H2O + urate/in
-
Homo sapiens ADP + phosphate + urate/out
-
?
7.6.2.2 ATP + H2O + urate/in MRP4 is the first secretory transporter identified in the bidirectional renal handling of urate and could be a potential drug target in the treatment of hyperuricaemia, regulation, overview Homo sapiens ADP + phosphate + urate/out
-
?
7.6.2.2 ATP + H2O + ursodeoxycholylglycine/in
-
Homo sapiens ADP + phosphate + ursodeoxycholylglycine/out
-
?
7.6.2.2 ATP + H2O + ursodeoxycholyltaurine/in
-
Homo sapiens ADP + phosphate + ursodeoxycholyltaurine/out
-
?
7.6.2.2 ATP + H2O + xenobiotic/in
-
Mus musculus ADP + phosphate + xenobiotic/out
-
?
7.6.2.2 ATP + H2O + xenobiotic/in
-
Homo sapiens ADP + phosphate + xenobiotic/out
-
?
7.6.2.2 ATP + H2O + xenobiotic/in in the brain, MRP4 limits the entry of drugs and is involved in nociception, probably as a result of reduced plasma prostaglandins. In the kidney, MRP4 mediates the active tubular secretion of diuretics, antiviral nucleosides and cephalosporins. In the liver, MRP4 mediates the efflux of bile acid to the blood, and knockout mice are more sensitive to cholestatic-induced liver injury. MRP4 protects bone marrow cells and the gastrointestinal tract against cytotoxic drugs and appears to be involved in secretory diarrhoea via coupling with CFTR Mus musculus ADP + phosphate + xenobiotic/out
-
?
7.6.2.2 ATP + H2O + xenobiotic/in MRP4 limits brain entry and promotes renal excretion of drugs. In addition to its role in the body distribution and renal excretion of a wide variety of antiviral, cytostatic, antibiotic and cardiovascular drugs, MRP4/ABCC4 has the ability to transport molecules involved in cellular signalling. These molecules include cyclic nucleotides, eicosanoids, urate and conjugated steroids. The unique structure, regulation and dual localisation of MRP4 in polarised cells could be connected with a key function in cellular protection and extracellular signalling pathways, overview Homo sapiens ADP + phosphate + xenobiotic/out
-
?
7.6.2.2 additional information substrate specificity, overview. Renal excretion is an important route of elimination for many MRP4 substrates. MRP4 has a putative pathophysiological function in signalling, and it protects the liver from accumulation of toxic bile acids during cholestasis by facilitating their efflux into blood for ultimate renal excretion Homo sapiens ?
-
?

Subunits

EC Number Subunits Comment Organism
7.6.2.2 More the enzyme structure shows multiple allosteric binding sites of MRP4, homology model of human MRP4: MRP4 has a typical ABC transporter core structure comprising two membrane-spanning domains, each consisting of six transmembrane helices with two cytosolic ATP-binding domains, which bind and hydrolyse ATP to power substrate transport Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
7.6.2.2 ABCC4
-
Mus musculus
7.6.2.2 ABCC4
-
Homo sapiens
7.6.2.2 More MRP4 is a member of the MRP/ABCC C subfamily of ATP-binding cassette transporters Mus musculus
7.6.2.2 More MRP4 is the shortest member of the MRP/ABCC C subfamily of ATP-binding cassette transporters Homo sapiens
7.6.2.2 MRP4
-
Mus musculus
7.6.2.2 MRP4
-
Homo sapiens
7.6.2.2 multidrug resistance protein 4
-
Mus musculus
7.6.2.2 multidrug resistance protein 4
-
Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
7.6.2.2 ATP
-
Mus musculus
7.6.2.2 ATP
-
Homo sapiens

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
7.6.2.2 0.001
-
-
Homo sapiens quercetin
7.6.2.2 0.001 0.012
-
Homo sapiens dipyridamole
7.6.2.2 0.002
-
-
Homo sapiens sulindac
7.6.2.2 0.002 0.01
-
Homo sapiens MK571
7.6.2.2 0.005 0.022
-
Homo sapiens indomethacin
7.6.2.2 0.01
-
-
Homo sapiens losartan
7.6.2.2 0.02
-
-
Homo sapiens sildenafil
7.6.2.2 0.035
-
-
Homo sapiens celecoxib
7.6.2.2 0.1
-
-
Homo sapiens probenecid
7.6.2.2 0.75
-
-
Homo sapiens 4-(2-aminoethyl)benzenesulfonylfluoride