TABLE 1

Endogenous and exogenous substrates of MRP4

Compound	System	In Vitro or In Vivo Kinetic Parameters/Drug Resistance/Cellular Efflux	Reference
Endogenous components
cAMP	Sf9-hMRP4; VT	Transport rate: 8 pmol/mg protein/min	van Aubel et al. (2002)
	Sf9-hMRP4; VT	K_m: 44.5 μM	Chen et al. (2001)
cGMP	Sf9-hMRP4; VT	Transport rate: 78 pmol/mg protein/min	van Aubel et al. (2002)
	Sf9-hMRP4; VT	K_m: 9.69 μM; transport rate: 2.0 pmol/mg protein/min	Chen et al. (2001)
	Sf9-hMRP4; VT	K_m: 180 μM; transport rate: 58 pmol/mg protein/min	Van Aubel et al. (2005)
ADP	Platelet-dense MVs; VT	Dipyridamole, indomethacin, and MK571 inhibit ADP uptake with the IC50 of 12, 22, and 43 μM	Jedlitschky et al. (2004)
Urate	Sf9-hMRP4; VT	K_m: 1550 μM; transport rate: 47 pmol/mg protein/min	Van Aubel et al. (2005)
E₂17βG	Sf9-hMRP4; VT	K_m: 30.3 μM; transport rate: 58 pmol/mg protein/ min	Chen et al. (2001)
DHEAS	Sf9-hMRP4; VT	K_m: 2 μM; transport rate: 45 pmol/mg protein/min	Zelcer et al. (2003)
Folic acid	Sf9-hMRP4; VT	K_m: 0.17 μM; transport rate: 0.68 nmol/mg protein/min	Chen et al. (2002)
LTB₄	V79- hMRP4; VT	K_m: 5.2 μM; transport rate: 9.88 pmol/mg protein/min^{^a}	Rius et al. (2008)
LTC₄	V79- hMRP4; VT	K_m: 0.13 μM; transport rate: 37.40 pmol/mg protein/min	Rius et al. (2008)
PGE₁	Sf9-hMRP4; VT	K_m: 2.1 μM; transport rate: 6.9 pmol/mg protein/min	Reid et al. (2003b)
PGE₂	Sf9-hMRP4; VT	K_m: 3.4 μM; transport rate: 6.4 pmol/mg protein/min	Reid et al. (2003b)
	V79-hMRP4; VT	K_m: 3.5 Mm; transport rate: 3.25 pmol/mg protein/min	Rius et al. (2005)
TXB2	V79-hMRP4; VT	9.9 μM; transport rate: 51 pmol/mg protein/min	Rius et al. (2005)
PEF₂_α	V79-hMRP4; VT	12.6 μM; transport rate: 46.1 pmol/mg protein/min	Rius et al. (2005)
7-Hydroxycoumarin-glucuronide	HEK293-hMRP4; VT	K_m: 63 μM; transport rate: 920 pmol/mg protein/min	Wittgen et al. (2012)
Cholate	V79-hMRP4; VT	K_m: 14.8 μM; transport rate: 75 pmol/mg protein/min^{^a}	Rius et al. (2006)
Cholylglycine	V79-hMRP4; VT	K_m: 25.8 μM; transport rate: 175 pmol/mg protein/min^{^a}	Rius et al. (2006)
Cholyltaurine	V79-hMRP4; VT	K_m: 7.7 μM; transport rate: 154 pmol/mg protein/min^{^a}	Rius et al. (2006)
Deoxycholylglycine	V79-hMRP4; VT	K_m: 6.7 μM; transport rate: 116 pmol/mg protein/min^{^a}	Rius et al. (2006)
Chenodeoxycholylglycine	V79-hMRP4; VT	K_m: 5.9 μM; transport rate: 93 pmol/mg protein/min^{^a}	Rius et al. (2006)
Chenodeoxycholyltaurine	V79-hMRP4; VT	K_m: 3.6 μM; transport rate: 83 pmol/mg protein/min^{^a}	Rius et al. (2006)
Ursodeoxycholylglycine	V79-hMRP4; VT	K_m: 12.5 ± 0.5 μM; transport rate: 130 pmol/mg protein/min^{^a}	Rius et al. (2006)
Ursodeoxycholyltaurine	V79-hMRP4; VT	K_m: 7.8 μM; transport rate: 133 pmol/mg protein/min^{^a}	Rius et al. (2006)
GSH	V79-hMRP4;VT	K_m: 1.0 μM; transport rate: 175 pmol/mg protein/min^{^b}	Rius et al. (2003)
Drugs and drug conjugates
Antineoplastic
Methotrexate	Sf9-hMRP4; VT	K_m: 0.22 mM; transport rate: 240 pmol/mg protein/min	Chen et al. (2002)
	Sf9-hMRP4; VT	K_m: 1.3 mM; transport rate: 430 pmol/mg protein/min	van Aubel et al. (2002)
	HEK293-hMRP4; VT	K_m: 220 μM; transport rate: 280 pmol/mg protein/min	El-Sheikh et al. (2007)
	MRP4-transfected NIH3T3; DRA	5.5-fold increased resistance to methotrexate	Lee et al. (2000)
Topotecan	HepG2 cells stably expressing MRP4; DRA	12.03- and 6.86-fold resistance to topotecan in the 4- and 48-hour drug exposure	Tian et al. (2006)
	Mrp4-KO mice; IDP	CSF topotecan concentration is 10-fold that of WT	Leggas et al. (2004)
	Saos 2-MRP4; DRA	5-fold more resistance to topotecan in 6 hour exposure	Leggas et al. (2004)
Leucovorin	Sf9-hMRP4; VT	K_m: 0.64 mM; transport rate: 1.95 nmol/mg protein/min	Chen et al. (2002)
Dasatinib	Sf9-hMRP4; VT	2-fold increase in dasatinib uptake	Zwaan et al. (2013)
	MRP4 KO mice; IDP	1.75-fold decrease in systemic exposure to oral dasatinib	Zwaan et al. (2013)
Cytarabine	HEK293-hMRP4; DRA	1.6-fold increase of drug resistance in MRP4 cells	Adema et al. (2014)
	MRP4 transfected HEK293; CE	2- to 3-fold decrease in MRP4 cells after 4-hour exposure of ara-C nucleotides	Adema et al. (2014)
6-MP, 6-TGN, and 6-TGMP	MRP4-transfected NIH3T3; DRA and CE	3.6-fold increase in 6-MP resistance and decreased cellular drug accumulation	Chen et al. (2001)
	bone marrow from MRP4 KO mice; IDP	Cellular concentration of 6-TGN and 6-TGMP was significantly higher	Krishnamurthy et al. (2008)
Troxacitabine	HEK293-hMRP4; DRA	1.8-fold increase in drug resistance	Adema et al. (2014)
	HEK293-hMRP4; CE	2- to 4-fold decrease in the rate of drug export after washing with drug-free medium	Adema et al. (2014)
Antivirals
Adefovir	MRP4-transfected NIH3T3; DRA	2.3-fold more resistance to continuous PMEA-exposure assays	Lee et al. (2000)
	HEK293-hMRP4;VT	K_m: >1 mM	Imaoka et al. (2007)
	MRP4-overexpressing (CEM-R1) cells; DRA	>8.5-fold increase in drug resistance	Ray et al. (2006)
	MEFs from Mrp4 KO mouse; CE	73% decrease in the rate of PMEA export	Imaoka et al. (2007)
	MRP KO mice; IDP	2-fold more drug accumulation in KO kidney	Ray et al. (2006)
Tenofovir	Sf9-hMRP4; VT	Transport rate: >2 pmol/mg protein/min	Ray et al. (2006)
	MRP4-overexpressing (CEM-R1) cells; DRA	1.0-fold increase in drug resistance	Imaoka et al. (2007)
	MRP4 KO mice; IDP	1-fold elevation in renal drug accumulation	Fukuda et al. (2013)
Nelfinavir	Saos-2 and HEK293-hMRP4; CE	Cellular PMEA concentration decreased after cotreatment with nelfinavir	Fukuda et al. (2013)
	MEFs from Mrp4 KO mouse; DRA and CE	7.6-fold increased sensitivity to nelfinavir toxicity strongly reduced the export of PMEA from WT MEFs	Lee et al. (2000)
Antibiotics
Ceftizoxime	HEK293-hMRP4; VT	K_m: 18.3 μM; transport rate: 529 pmol/mg protein/min	Ci et al. (2007)
	MRP4 KO mice; IDP	2.0-fold elevation in kidney-to-plasma concentration ratio of ceftizoxime	Ci et al. (2007)
Cefazolin	HEK293-hMRP4; VT	K_m: 80.9 μM; transport rate: 3240 pmol/mg protein/min	Ci et al. (2007)
	MRP4 KO mice; IDP	2.7-fold elevation in kidney-to-plasma concentration ratio of ceftizoxime	Ci et al. (2007)
Cefotaxime	HEK293-hMRP4; VT	—	Ci et al. (2007)
Cefmetazole	HEK293-hMRP4; VT	—	Ci et al. (2007)
	Sf9-hMRP4; VT	K_m: 28.5 μM; transport rate: 914 pmol/mg protein/min	Uchida et al. (2007)
Cefadroxil	Sf21-hMRP4; VT	K_m: 0.25 mM	de Waart et al. (2012)
	Ex vivo transport chamber	50% decrease in cefadroxil transport	de Waart et al. (2012)
	Abcc3^−/−/Abcc4^−/− mice; IDP	Cefadroxil concentration in portal artery was only decreased in both abcc3 and 4 KO mice	de Waart et al. (2012)
Cardiovascular drugs
Hydrochlorothiazide	HEK293-hMRP4; VT	—	Hasegawa et al. (2007)
	MRP4 KO mice; IDP	40% decrease in renal clearance	Hasegawa et al. (2007)
Furosemide	HEK293-hMRP4; VT	—	Hasegawa et al. (2007)
	MRP4 KO mice; IDP	30% decrease in renal clearance	Hasegawa et al. (2007)
Olmesartan	HEK293-hMRP4; VT	K_m: 26.2 μM; transport rate: 195 pmol/mg protein/min	Yamada et al. (2007)
Enalaprilat	HEK293T-hMRP4; VT	3.8-fold increase in drug uptake into MV	Ferslew et al. (2014)
	Sandwich-cultured hepatocyte; CE	65% decrease in basolateral efflux clearance by pretreatment with MK571	Ferslew et al. (2014)
Other drugs
Mycophenolic acid	HEK293-hMRP4; CE	MRP4-mediated MPA efflux is 2× greater than control levels	El-Sheikh et al. (2014)
	MRP4 KO mice; IDP	Urinary excretion was significantly greater in kidneys of WT mice compared MRP4-deficient mice	El-Sheikh et al. (2014)
Edaravone glucuronide	HEK293-hMRP4; VT	K_m: 9.85 μM; transport rate: 3512 pmol/mg protein/min	Mizuno et al. (2007)
PAH	Sf9-hMRP4; VT	K_m: 160 μM; transport rate: 80 pmol/mg protein/min	Smeets et al. (2004)
d-Luciferin	SK-N-BE(2) luc⁺ expressing mouse MRP4; CE	60% decrease in bioluminescence compared with parental cells	Cheung et al. (2015)
	HEK293- MRP4 luc⁺ cells; DRA	3- to 5-fold increase in bioluminescence by MRP4 inhibitors MK571 and dipyridamole	Cheung et al. (2015)
Toxic chemicals
DMA^V	HEK293T-hMRP4; VT	K_m: 0.22 μM; transport rate: 32 pmol/mg protein/min	Banerjee et al. (2014)
MMA(GS)2	HEK293T-hMRP4; VT	K_m: 0.70 μM; transport rate: 112 pmol/mg protein/min	Banerjee et al. (2014)
DDT	LLC-PK1-zMRP4; VT	Decrease in cytotoxicity and cellular accumulation	Lu et al. (2014)
Lindane	LLC-PK1-zMRP4; VT	Decrease in cytotoxicity and cellular accumulation	Lu et al. (2014)

CE, cellular efflux; CSF, cerebrospinal fluid; DDT, dichloro diphenyl trichloroethane; DHEAS, dehydroepiandrosterone 3-sulfate; DMA^V, dimethylarsinic acid; DRA, drug resistance assay; IDP: in vivo pharmacokinetics; LTC₄, leukotriene C₄; MEF, mouse embryo fibroblast; MMA(GS)2, diglutathione conjugate of monomethylarsonous acid; PAH, p-aminohippurate; PEF₂_α, prostaglandin F₂_α; PGE₁, prostaglandin E₁; PMEA, adefovir dipivoxil; 6-TGMP, 6-thioguanine monophosphate; 6-TGN, 6-thioguanine nucleotide; TXB2, thromboxane B2; VT, vesicular transport.
↵^a In presence of 5 mM GSH.
↵^b In the presence of 5 μM cholyltaurine.