Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTALGS63)

• DOT Name: Phospholipid-transporting ATPase IC (ATP8B1)
• Synonyms: EC 7.6.2.1; ATPase class I type 8B member 1; Familial intrahepatic cholestasis type 1; P4-ATPase flippase complex alpha subunit ATP8B1
• Gene Name: ATP8B1
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Progressive familial intrahepatic cholestasis type 1
  Alagille syndrome
  Cholangiocarcinoma
  Colorectal carcinoma
  Cystic fibrosis
  Hypothyroidism
  Intrahepatic cholestasis of pregnancy
  Liver cirrhosis
  Liver failure
  Malabsorption syndrome
  Pancreatitis
  Paroxysmal nocturnal haemoglobinuria
  Progressive familial intrahepatic cholestasis
  Progressive familial intrahepatic cholestasis type 3
  Pulmonary fibrosis
  Acute myelogenous leukaemia
  Cholestasis, intrahepatic, of pregnancy, 1
  Chronic diarrhoea
  Diarrhea
  Fatty liver disease
  Intrahepatic cholestasis
  Vibrio cholerae infection
• UniProt ID: AT8B1_HUMAN
• PDB ID: 7PY4; 7VGH; 7VGI; 7VGJ; 8OX4; 8OX5; 8OX6; 8OX7; 8OX8; 8OX9; 8OXA; 8OXB; 8OXC
• EC Number: 7.6.2.1
• Pfam ID: PF13246 ; PF00122 ; PF16212 ; PF16209
• Sequence:
  MSTERDSETTFDEDSQPNDEVVPYSDDETEDELDDQGSAVEPEQNRVNREAEENREPFRK
  ECTWQVKANDRKYHEQPHFMNTKFLCIKESKYANNAIKTYKYNAFTFIPMNLFEQFKRAA
  NLYFLALLILQAVPQISTLAWYTTLVPLLVVLGVTAIKDLVDDVARHKMDKEINNRTCEV
  IKDGRFKVAKWKEIQVGDVIRLKKNDFVPADILLLSSSEPNSLCYVETAELDGETNLKFK
  MSLEITDQYLQREDTLATFDGFIECEEPNNRLDKFTGTLFWRNTSFPLDADKILLRGCVI
  RNTDFCHGLVIFAGADTKIMKNSGKTRFKRTKIDYLMNYMVYTIFVVLILLSAGLAIGHA
  YWEAQVGNSSWYLYDGEDDTPSYRGFLIFWGYIIVLNTMVPISLYVSVEVIRLGQSHFIN
  WDLQMYYAEKDTPAKARTTTLNEQLGQIHYIFSDKTGTLTQNIMTFKKCCINGQIYGDHR
  DASQHNHNKIEQVDFSWNTYADGKLAFYDHYLIEQIQSGKEPEVRQFFFLLAVCHTVMVD
  RTDGQLNYQAASPDEGALVNAARNFGFAFLARTQNTITISELGTERTYNVLAILDFNSDR
  KRMSIIVRTPEGNIKLYCKGADTVIYERLHRMNPTKQETQDALDIFANETLRTLCLCYKE
  IEEKEFTEWNKKFMAASVASTNRDEALDKVYEEIEKDLILLGATAIEDKLQDGVPETISK
  LAKADIKIWVLTGDKKETAENIGFACELLTEDTTICYGEDINSLLHARMENQRNRGGVYA
  KFAPPVQESFFPPGGNRALIITGSWLNEILLEKKTKRNKILKLKFPRTEEERRMRTQSKR
  RLEAKKEQRQKNFVDLACECSAVICCRVTPKQKAMVVDLVKRYKKAITLAIGDGANDVNM
  IKTAHIGVGISGQEGMQAVMSSDYSFAQFRYLQRLLLVHGRWSYIRMCKFLRYFFYKNFA
  FTLVHFWYSFFNGYSAQTAYEDWFITLYNVLYTSLPVLLMGLLDQDVSDKLSLRFPGLYI
  VGQRDLLFNYKRFFVSLLHGVLTSMILFFIPLGAYLQTVGQDGEAPSDYQSFAVTIASAL
  VITVNFQIGLDTSYWTFVNAFSIFGSIALYFGIMFDFHSAGIHVLFPSAFQFTGTASNAL
  RQPYIWLTIILAVAVCLLPVVAIRFLSMTIWPSESDKIQKHRKRLKAEEQWQRRQQVFRR
  GVSTRRSAYAFSHQRGYADLISSGRSIRKKRSPLDAIVADGTAEYRRTGDS
• Function: Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane. May participate in the establishment of the canalicular membrane integrity by ensuring asymmetric distribution of phospholipids in the canicular membrane. Thus may have a role in the regulation of bile acids transport into the canaliculus, uptake of bile acids from intestinal contents into intestinal mucosa or both and protect hepatocytes from bile salts. Involved in the microvillus formation in polarized epithelial cells; the function seems to be independent from its flippase activity. Participates in correct apical membrane localization of CDC42, CFTR and SLC10A2. Enables CDC42 clustering at the apical membrane during enterocyte polarization through the interaction between CDC42 polybasic region and negatively charged membrane lipids provided by ATP8B1. Together with TMEM30A is involved in uptake of the synthetic drug alkylphospholipid perifosine. Required for the preservation of cochlear hair cells in the inner ear. May act as cardiolipin transporter during inflammatory injury.
• Tissue Specificity: Found in most tissues except brain and skeletal muscle. Most abundant in pancreas and small intestine.
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Genetic Variation	[1]
Liver cancer	DISDE4BI	Definitive	Genetic Variation	[1]
Progressive familial intrahepatic cholestasis type 1	DISU0AJE	Definitive	Autosomal recessive	[2]
Alagille syndrome	DIS9DPU8	Strong	Biomarker	[3]
Cholangiocarcinoma	DIS71F6X	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[6]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[7]
Intrahepatic cholestasis of pregnancy	DISMHS5F	Strong	Genetic Variation	[8]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[9]
Liver failure	DISLGEL6	Strong	Genetic Variation	[10]
Malabsorption syndrome	DISGMUVS	Strong	Biomarker	[11]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[12]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Genetic Variation	[13]
Progressive familial intrahepatic cholestasis	DIS3J8HT	Strong	Biomarker	[14]
Progressive familial intrahepatic cholestasis type 3	DISVT2LV	Strong	Genetic Variation	[15]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[16]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[17]
Cholestasis, intrahepatic, of pregnancy, 1	DISDFNT4	Limited	Unknown	[18]
Chronic diarrhoea	DISH3PX3	Limited	Biomarker	[19]
Diarrhea	DISWTJQL	Limited	Biomarker	[20]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[21]
Intrahepatic cholestasis	DISHITDZ	Limited	Genetic Variation	[22]
Vibrio cholerae infection	DISW7E3U	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[27]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[28]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[29]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[30]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[31]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[32]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[33]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[34]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[35]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[32]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[36]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[40]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Phospholipid-transporting ATPase IC (ATP8B1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phospholipid-transporting ATPase IC (ATP8B1).	[38]

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