Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO27PAL)

• DOT Name: ATP-binding cassette sub-family C member 4 (ABCC4)
• Synonyms: EC 7.6.2.-; EC 7.6.2.2; EC 7.6.2.3; MRP/cMOAT-related ABC transporter; Multi-specific organic anion transporter B; MOAT-B; Multidrug resistance-associated protein 4
• Gene Name: ABCC4
• Related Disease: Qualitative platelet defect
• UniProt ID: MRP4_HUMAN
• PDB ID: 8BJF; 8BWO; 8BWP; 8BWQ; 8BWR; 8I4A; 8I4B; 8I4C; 8J3W; 8J3Z
• EC Number: 7.6.2.-; 7.6.2.2; 7.6.2.3
• Pfam ID: PF00664 ; PF00005
• 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: ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins. Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4. Mediates the cotransport of bile acids with reduced glutathione (GSH). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules. Confers resistance to anticancer agents such as methotrexate.
• Tissue Specificity: Widely expressed, with particularly high levels in prostate, but is barely detectable in liver. sinusoidal membrane of hepatocytes.
• KEGG Pathway:
  Antifolate resistance (hsa01523)
  ABC transporters (hsa02010)
  cAMP sig.ling 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)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Qualitative platelet defect	DISNG54P	Moderate	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 19 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Arsenic.	[39]
Ampicillin	DMHWE7P	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Ampicillin.	[40]
Bezafibrate	DMZDCS0	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Bezafibrate.	[40]
Glutathione	DMAHMT9	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) affects the transport of Glutathione.	[42]
Tetracycline	DMZA017	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Tetracycline.	[40]
Furosemide	DMMQ8ZG	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Furosemide.	[40]
Enalapril	DMNFUZR	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Enalapril.	[40]
Hydrochlorothiazide	DMUSZHD	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Hydrochlorothiazide.	[40]
Bumetanide	DMRV7H0	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Bumetanide.	[40]
Baclofen	DM0QV1J	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Baclofen.	[40]
Ceftazidime	DM41GRA	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Ceftazidime.	[40]
Benzylpenicillin	DMS9503	Phase 3	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Benzylpenicillin.	[40]
Rebamipide	DM2GHCR	Phase 3	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Rebamipide.	[40]
[3H]cAMP	DMZRQU7	Investigative	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of [3H]cAMP.	[43]
Uric acid	DMA1MKT	Investigative	ATP-binding cassette sub-family C member 4 (ABCC4) affects the export of Uric acid.	[44]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	ATP-binding cassette sub-family C member 4 (ABCC4) increases the export of Hydroxydimethylarsine Oxide.	[45]
Cyclic guanosine monophosphate	DMOU93V	Investigative	ATP-binding cassette sub-family C member 4 (ABCC4) increases the export of Cyclic guanosine monophosphate.	[41]
PMEA	DMBKVJY	Investigative	ATP-binding cassette sub-family C member 4 (ABCC4) increases the export of PMEA.	[46]
Cephalosporin C	DMYW3ZG	Investigative	ATP-binding cassette sub-family C member 4 (ABCC4) increases the transport of Cephalosporin C.	[40]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) increases the hydrolysis of Adenosine triphosphate.	[41]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Meloxicam	DM2AR7L	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) affects the binding of Meloxicam.	[40]
Nateglinide	DMLK2QH	Approved	ATP-binding cassette sub-family C member 4 (ABCC4) affects the binding of Nateglinide.	[40]
Resveratrol	DM3RWXL	Phase 3	ATP-binding cassette sub-family C member 4 (ABCC4) decreases the response to substance of Resveratrol.	[41]

38 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[16]
Aspirin	DM672AH	Approved	Aspirin increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[18]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[19]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[20]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[21]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[12]
Dipyridamole	DMXY30O	Approved	Dipyridamole decreases the activity of ATP-binding cassette sub-family C member 4 (ABCC4).	[22]
Tolvaptan	DMIWFRL	Approved	Tolvaptan decreases the activity of ATP-binding cassette sub-family C member 4 (ABCC4).	[23]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[25]
Triptolide	DMCMDVR	Phase 3	Triptolide decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[26]
TAK-875	DMIM5AP	Phase 3	TAK-875 decreases the activity of ATP-binding cassette sub-family C member 4 (ABCC4).	[27]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[30]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[32]
PMID26560530-Compound-34	DMLGZPO	Patented	PMID26560530-Compound-34 increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[33]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[35]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[36]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[37]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[38]
6-bromoindirubin-3-oxime	DM12WYV	Investigative	6-bromoindirubin-3-oxime increases the expression of ATP-binding cassette sub-family C member 4 (ABCC4).	[10]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ATP-binding cassette sub-family C member 4 (ABCC4).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of ATP-binding cassette sub-family C member 4 (ABCC4).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATP-binding cassette sub-family C member 4 (ABCC4).	[34]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of ATP-binding cassette sub-family C member 4 (ABCC4).	[31]

References

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