Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUEAFL)

DTT Name	Multidrug resistance protein 4 (ABCC4)
Synonyms	Multispecific organic anion transporter B; Multidrug resistanceassociated protein 4; MRP/cMOATrelated ABC transporter; MOATB; ATPbinding cassette subfamily C member 4; ABCC4
Gene Name	ABCC4
DTT Type	Literature-reported target	[1]
BioChemical Class	ABC transporter
UniProt ID	MRP4_HUMAN
TTD ID	T39919
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Sequence	MLPVYQEVKPNPLQDANLCSRVFFWWLNPLFKIGHKRRLEEDDMYSVLPEDRSQHLGEEL QGFWDKEVLRAENDAQKPSLTRAIIKCYWKSYLVLGIFTLIEESAKVIQPIFLGKIINYF ENYDPMDSVALNTAYAYATVLTFCTLILAILHHLYFYHVQCAGMRLRVAMCHMIYRKALR LSNMAMGKTTTGQIVNLLSNDVNKFDQVTVFLHFLWAGPLQAIAVTALLWMEIGISCLAG MAVLIILLPLQSCFGKLFSSLRSKTATFTDARIRTMNEVITGIRIIKMYAWEKSFSNLIT NLRKKEISKILRSSCLRGMNLASFFSASKIIVFVTFTTYVLLGSVITASRVFVAVTLYGA VRLTVTLFFPSAIERVSEAIVSIRRIQTFLLLDEISQRNRQLPSDGKKMVHVQDFTAFWD KASETPTLQGLSFTVRPGELLAVVGPVGAGKSSLLSAVLGELAPSHGLVSVHGRIAYVSQ QPWVFSGTLRSNILFGKKYEKERYEKVIKACALKKDLQLLEDGDLTVIGDRGTTLSGGQK ARVNLARAVYQDADIYLLDDPLSAVDAEVSRHLFELCICQILHEKITILVTHQLQYLKAA SQILILKDGKMVQKGTYTEFLKSGIDFGSLLKKDNEESEQPPVPGTPTLRNRTFSESSVW SQQSSRPSLKDGALESQDTENVPVTLSEENRSEGKVGFQAYKNYFRAGAHWIVFIFLILL NTAAQVAYVLQDWWLSYWANKQSMLNVTVNGGGNVTEKLDLNWYLGIYSGLTVATVLFGI ARSLLVFYVLVNSSQTLHNKMFESILKAPVLFFDRNPIGRILNRFSKDIGHLDDLLPLTF LDFIQTLLQVVGVVSVAVAVIPWIAIPLVPLGIIFIFLRRYFLETSRDVKRLESTTRSPV FSHLSSSLQGLWTIRAYKAEERCQELFDAHQDLHSEAWFLFLTTSRWFAVRLDAICAMFV IIVAFGSLILAKTLDAGQVGLALSYALTLMGMFQWCVRQSAEVENMMISVERVIEYTDLE KEAPWEYQKRPPPAWPHEGVIIFDNVNFMYSPGGPLVLKHLTALIKSQEKVGIVGRTGAG KSSLISALFRLSEPEGKIWIDKILTTEIGLHDLRKKMSIIPQEPVLFTGTMRKNLDPFNE HTDEELWNALQEVQLKETIEDLPGKMDTELAESGSNFSVGQRQLVCLARAILRKNQILII DEATANVDPRTDELIQKKIREKFAHCTVLTIAHRLNTIIDSDKIMVLDSGRLKEYDEPYV LLQNKESLFYKMVQQLGKAEAAALTETAKQVYFKRNYPHIGHTDHMVTNTSNGQPSTLTI FETAL
Function	May be an organic anion pump relevant to cellular detoxification.
KEGG Pathway	Antifolate resistance (hsa01523 ) ABC transporters (hsa02010 ) cAMP signaling pathway (hsa04024 ) Bile secretion (hsa04976 )
Reactome Pathway	ABC-family proteins mediated transport (R-HSA-382556 ) Azathioprine ADME (R-HSA-9748787 ) Paracetamol ADME (R-HSA-9753281 ) Platelet degranulation (R-HSA-114608 )

The Drug Transporter (DTP) Role of This DTT

DTT DTP Name

Multidrug resistance-associated protein 4 (ABCC4) DTP Info

Gene Name

ABCC4

29 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Abacavir	DMMN36E	Human immunodeficiency virus infection	1C62	Approved	[2]
Adefovir	DMM278X	Hepatitis B virus infection	1E51.0	Approved	[3]
Alprostadil	DMWH7NQ	Diabetic foot ulcer	BD54	Approved	[4]
Cefadroxil	DMMC345	Bacterial infection	1A00-1C4Z	Approved	[5]
Cefazolin	DMPDYFR	Bacterial infection	1A00-1C4Z	Approved	[5]
Ceftizoxime	DM3VOGS	Bacterial infection	1A00-1C4Z	Approved	[5]
Cholic acid	DM7OKQV	Peroxisomal disorder	5C57	Approved	[2]
Ciprofloxacin XR	DM2NLS9	Bacterial infection	1A00-1C4Z	Approved	[6]
Cladribine	DM3JDRP	Hairy cell leukaemia	2A82.2	Approved	[2]
Cyclophosphamide	DM4O2Z7	Solid tumour/cancer	2A00-2F9Z	Approved	[7]
Dehydroepiandrosterone sulfate	DM4Q80H	Dyspareunia	GA12	Approved	[8]
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[4]
Fluorouracil	DMUM7HZ	Solid tumour/cancer	2A00-2F9Z	Approved	[9]
Folic acid	DMEMBJC	Folate-deficiency anemia	3A02.Y	Approved	[10]
Ganciclovir	DM1MBYQ	Virus infection	1A24-1D9Z	Approved	[2]
Glutathione	DMAHMT9	Human immunodeficiency virus infection	1C62	Approved	[11]
Irinotecan	DMP6SC2	Colorectal cancer	2B91.Z	Approved	[12]
Leucovorin	DMUAZWG	Colorectal cancer	2B91.Z	Approved	[10]
Mercaptopurine	DMTM2IK	Acute lymphoblastic leukaemia	2A85	Approved	[13]
Methotrexate	DM2TEOL	leukaemia	2A60-2B33	Approved	[14]
Olmesartan medoxomil	DMWBHRY	High blood pressure	BA00	Approved	[15]
Oseltamivir	DMGO72P	Influenza virus infection	1E30-1E32	Approved	[16]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[8]
Quercetin	DM3NC4M	Obesity	5B81	Approved	[2]
Sulindac	DM2QHZU	Rheumatoid arthritis	FA20	Approved	[17]
Tenofovir	DM1IS6U	Human immunodeficiency virus infection	1C62	Approved	[3]
Thioguanine	DM7NKEV	Acute myeloid leukaemia	2A60	Approved	[18]
Topotecan	DMP6G8T	Ovarian cancer	2C73	Approved	[19]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[2]
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⏷ Show the Full List of 29 Approved Drug(s)

6 Clinical Trial Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Camptothecin	DM6CHNJ	Solid tumour/cancer	2A00-2F9Z	Phase 3	[2]
Resveratrol	DM3RWXL	Giant cell arteritis	4A44.2	Phase 3	[2]
Rubitecan	DMDWU1S	Human immunodeficiency virus infection	1C62	Phase 3	[2]
LE-SN38	DMW50NF	Colorectal cancer	2B91.Z	Phase 2	[2]
Taurocholic acid	DM2LZ8F	Type-2 diabetes	5A11	Phase 1/2	[2]
PGF2alpha	DM4XAU7	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[2]
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⏷ Show the Full List of 6 Clinical Trial Drug(s)

1 Preclinical Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Azidothymidine monophosphate	DM3FLMR	Solid tumour/cancer	2A00-2F9Z	Preclinical	[20]
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7 Investigative Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
10-hydroxycamptothecin	DM9WLN4	Discovery agent	N.A.	Investigative	[2]
4-(2-Aminoethyl) benzenesulfonyl fluoride	DMWHDRI	Discovery agent	N.A.	Investigative	[17]
Aminohippuric acid	DMUN54G	Discovery agent	N.A.	Investigative	[21]
Glycocholic acid	DM0SXNM	Discovery agent	N.A.	Investigative	[2]
Glycodeoxycholic acid	DM1XEJV	Discovery agent	N.A.	Investigative	[2]
[3H]cAMP	DMZRQU7	Discovery agent	N.A.	Investigative	[22]
[3H]estradiol-17beta-glucuronide	DM3KJ45	Discovery agent	N.A.	Investigative	[23]
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⏷ Show the Full List of 7 Investigative Drug(s)

References

1	High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4). Biochem Pharmacol. 2014 Sep 1;91(1):97-108.
2	Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
3	Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol. 2007 Feb;71(2):619-27.
4	The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9.
5	Oral availability of cefadroxil depends on ABCC3 and ABCC4. Drug Metab Dispos. 2012 Mar;40(3):515-21.
6	Identification of the efflux transporter of the fluoroquinolone antibiotic ciprofloxacin in murine macrophages: studies with ciprofloxacin-resistant cells. Antimicrob Agents Chemother. 2009 Jun;53(6):2410-6.
7	Interaction of oxazaphosphorines with multidrug resistance-associated protein 4 (MRP4). AAPS J. 2010 Sep;12(3):300-8.
8	Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochem J. 2003 Apr 15;371(Pt 2):361-7.
9	ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology. 2009;9(1-2):136-44.
10	Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 2002 Jun 1;62(11):3144-50.
11	Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues. Biochem J. 2002 Feb 1;361(Pt 3):497-503.
12	P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice. Drug Metab Lett. 2010 Dec;4(4):195-201.
13	Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood. 2009 Aug 13;114(7):1383-6.
14	Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J Pharmacol Exp Ther. 2007 Jan;320(1):229-35.
15	Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos. 2007 Dec;35(12):2166-76.
16	Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009 Feb;37(2):315-21.
17	Fluo-cAMP is transported by multidrug resistance-associated protein isoform 4 in rat choroid plexus. J Neurochem. 2010 Oct;115(1):200-8.
18	Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57.
19	Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab. 2006 Jan;7(1):105-18.
20	MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 1999 Sep;5(9):1048-51.
21	Contribution of multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter. J Am Soc Nephrol. 2004 Nov;15(11):2828-35.
22	cAMP regulates expression of the cyclic nucleotide transporter MRP4 (ABCC4) through the EPAC pathway. Pharmacogenet Genomics. 2014 Oct;24(10):522-6.
23	Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.