Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE6PY83)

• DOT Name: Phosphatidylcholine translocator ABCB4 (ABCB4)
• Synonyms: EC 7.6.2.1; ATP-binding cassette sub-family B member 4; Multidrug resistance protein 3; P-glycoprotein 3
• Gene Name: ABCB4
• Related Disease:
  Low phospholipid associated cholelithiasis
  Progressive familial intrahepatic cholestasis type 3
  Pancreatitis
• UniProt ID: MDR3_HUMAN
• PDB ID: 6S7P; 7NIU; 7NIV; 7NIW
• EC Number: 7.6.2.1
• Pfam ID: PF00664 ; PF00005
• Sequence:
  MDLEAAKNGTAWRPTSAEGDFELGISSKQKRKKTKTVKMIGVLTLFRYSDWQDKLFMSLG
  TIMAIAHGSGLPLMMIVFGEMTDKFVDTAGNFSFPVNFSLSLLNPGKILEEEMTRYAYYY
  SGLGAGVLVAAYIQVSFWTLAAGRQIRKIRQKFFHAILRQEIGWFDINDTTELNTRLTDD
  ISKISEGIGDKVGMFFQAVATFFAGFIVGFIRGWKLTLVIMAISPILGLSAAVWAKILSA
  FSDKELAAYAKAGAVAEEALGAIRTVIAFGGQNKELERYQKHLENAKEIGIKKAISANIS
  MGIAFLLIYASYALAFWYGSTLVISKEYTIGNAMTVFFSILIGAFSVGQAAPCIDAFANA
  RGAAYVIFDIIDNNPKIDSFSERGHKPDSIKGNLEFNDVHFSYPSRANVKILKGLNLKVQ
  SGQTVALVGSSGCGKSTTVQLIQRLYDPDEGTINIDGQDIRNFNVNYLREIIGVVSQEPV
  LFSTTIAENICYGRGNVTMDEIKKAVKEANAYEFIMKLPQKFDTLVGERGAQLSGGQKQR
  IAIARALVRNPKILLLDEATSALDTESEAEVQAALDKAREGRTTIVIAHRLSTVRNADVI
  AGFEDGVIVEQGSHSELMKKEGVYFKLVNMQTSGSQIQSEEFELNDEKAATRMAPNGWKS
  RLFRHSTQKNLKNSQMCQKSLDVETDGLEANVPPVSFLKVLKLNKTEWPYFVVGTVCAIA
  NGGLQPAFSVIFSEIIAIFGPGDDAVKQQKCNIFSLIFLFLGIISFFTFFLQGFTFGKAG
  EILTRRLRSMAFKAMLRQDMSWFDDHKNSTGALSTRLATDAAQVQGATGTRLALIAQNIA
  NLGTGIIISFIYGWQLTLLLLAVVPIIAVSGIVEMKLLAGNAKRDKKELEAAGKIATEAI
  ENIRTVVSLTQERKFESMYVEKLYGPYRNSVQKAHIYGITFSISQAFMYFSYAGCFRFGA
  YLIVNGHMRFRDVILVFSAIVFGAVALGHASSFAPDYAKAKLSAAHLFMLFERQPLIDSY
  SEEGLKPDKFEGNITFNEVVFNYPTRANVPVLQGLSLEVKKGQTLALVGSSGCGKSTVVQ
  LLERFYDPLAGTVFVDFGFQLLDGQEAKKLNVQWLRAQLGIVSQEPILFDCSIAENIAYG
  DNSRVVSQDEIVSAAKAANIHPFIETLPHKYETRVGDKGTQLSGGQKQRIAIARALIRQP
  QILLLDEATSALDTESEKVVQEALDKAREGRTCIVIAHRLSTIQNADLIVVFQNGRVKEH
  GTHQQLLAQKGIYFSMVSVQAGTQNL
• Function: [Isoform 1]: Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts. Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to further enrichment of SM and cholesterol in raft membranes in hepatocytes. Required for proper phospholipid bile formation. Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP-dependent manner. Promotes biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane. In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts. Does not confer multidrug resistance.
• KEGG Pathway:
  ABC transporters (hsa02010)
  Bile secretion (hsa04976)
• Reactome Pathway:
  ABC-family proteins mediated transport (R-HSA-382556)
  Defective ABCB4 causes PFIC3, ICP3 and GBD1 (R-HSA-5678771)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Low phospholipid associated cholelithiasis	DISKWFFA	Definitive	Semidominant	[1]
Progressive familial intrahepatic cholestasis type 3	DISVT2LV	Definitive	Autosomal recessive	[2]
Pancreatitis	DIS0IJEF	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Phosphatidylcholine translocator ABCB4 (ABCB4) decreases the response to substance of Paclitaxel.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Phosphatidylcholine translocator ABCB4 (ABCB4).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylcholine translocator ABCB4 (ABCB4).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[15]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[16]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[17]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[18]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Ritonavir	DMU764S	Approved	Ritonavir decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[20]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[21]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[22]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[23]
Omeprazole	DM471KJ	Approved	Omeprazole decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[24]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[25]
Lapatinib	DM3BH1Y	Approved	Lapatinib decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Flutamide	DMK0O7U	Approved	Flutamide decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Methoxsalen	DME8FZ9	Approved	Methoxsalen decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[26]
Loratadine	DMF3AN7	Approved	Loratadine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Benzbromarone	DMC3YUA	Approved	Benzbromarone decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Zafirlukast	DMHNQOG	Approved	Zafirlukast decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Perhexiline	DMINO7Z	Approved	Perhexiline decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Primaquine	DMWQ16I	Approved	Primaquine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Nortriptyline	DM4KDYJ	Approved	Nortriptyline decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Phentolamine	DMXYJOB	Approved	Phentolamine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Pazopanib	DMF57DM	Approved	Pazopanib decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Procyclidine	DMHFJDT	Approved	Procyclidine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Penbutolol	DM4ES8F	Approved	Penbutolol decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Tacrine	DM51FY6	Approved	Tacrine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Phenoxybenzamine	DM8KSQH	Approved	Phenoxybenzamine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Paliperidone	DM7NPJS	Approved	Paliperidone decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Biperiden	DME78OA	Approved	Biperiden decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Luvox	DMJKROX	Approved	Luvox decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Labetalol	DMK8U72	Approved	Labetalol decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Protriptyline	DMNHTZI	Approved	Protriptyline decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Hydroxyzine	DMF8Y74	Approved	Hydroxyzine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Chlorpheniramine	DM5URA2	Approved	Chlorpheniramine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Nitrofurantoin	DM7PQIK	Approved	Nitrofurantoin decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Tamsulosin	DM5QF9V	Approved	Tamsulosin decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Tipranavir	DM8HJX6	Approved	Tipranavir decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Guanethidine	DM9NSWT	Approved	Guanethidine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Clemastine	DMBZWQL	Approved	Clemastine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Tasosartan	DMM13DI	Approved	Tasosartan decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Methysergide	DM1EF73	Approved	Methysergide decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Doxylamine	DMKOXFE	Approved	Doxylamine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[11]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[26]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
ZIMELIDINE	DMNI3U2	Withdrawn from market	ZIMELIDINE decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Nomifensine	DMCP2TS	Withdrawn from market	Nomifensine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Ebrotidine	DMV5KR3	Withdrawn from market	Ebrotidine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Phosphatidylcholine translocator ABCB4 (ABCB4).	[31]
Oxybutynine	DMJPBAX	Investigative	Oxybutynine decreases the activity of Phosphatidylcholine translocator ABCB4 (ABCB4).	[19]

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