Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCWLX6N)

• DOT Name: ABC-type organic anion transporter ABCA8 (ABCA8)
• Synonyms: EC 7.6.2.-; ATP-binding cassette sub-family A member 8
• Gene Name: ABCA8
• UniProt ID: ABCA8_HUMAN
• EC Number: 7.6.2.-
• Pfam ID: PF12698 ; PF00005
• Sequence:
  MRKRKISVCQQTWALLCKNFLKKWRMKRESLMEWLNSLLLLLCLYIYPHSHQVNDFSSLL
  TMDLGRVDTFNESRFSVVYTPVTNTTQQIMNKVASTPFLAGKEVLGLPDEESIKEFTANY
  PEEIVRVTFTNTYSYHLKFLLGHGMPAKKEHKDHTAHCYETNEDVYCEVSVFWKEGFVAL
  QAAINAAIIEITTNHSVMEELMSVTGKNMKMHSFIGQSGVITDLYLFSCIISFSSFIYYA
  SVNVTRERKRMKALMTMMGLRDSAFWLSWGLLYAGFIFIMALFLALVIRSTQFIILSGFM
  VVFSLFLLYGLSLVALAFLMSILVKKSFLTGLVVFLLTVFWGCLGFTSLYRHLPASLEWI
  LSLLSPFAFMLGMAQLLHLDYDLNSNAFPHPSDGSNLIVATNFMLAFDTCLYLALAIYFE
  KILPNEYGHRRPPLFFLKSSFWSQTQKTDHVALEDEMDADPSFHDSFEQAPPEFQGKEAI
  RIRNVTKEYKGKPDKIEALKDLVFDIYEGQITAILGHSGAGKSTLLNILSGLSVPTKGSV
  TIYNNKLSEMADLENLSKLTGVCPQSNVQFDFLTVRENLRLFAKIKGILPQEVDKEIQRV
  LLELEMKNIQDVLAQNLSGGQKRKLTFGIAILGDPQIFLLDEPTAGLDPFSRHQVWNLLK
  ERKTDRVILFSTQFMDEADILADRKVFLSQGKLKCAGSSLFLKKKWGIGYHLSLQLNEIC
  VEENITSLVKQHIPDAKLSAKSEGKLIYTLPLERTNKFPELYKDLDSYPDLGIENYGVSM
  TTLNEVFLKLEGKSTINESDIAILGEVQAEKADDTERLVEMEQVLSSLNKMRKTIGGVAL
  WRQQICAIARVRLLKLKHERKALLALLLILMAGFCPLLVEYTMVKIYQNSYTWELSPHLY
  FLAPGQQPHDPLTQLLIINKTGASIDDFIQSVEHQNIALEVDAFGTRNGTDDPSYNGAIT
  VCCNEKNYSFSLACNAKRLNCFPVLMDIVSNGLLGMVKPSVHIRTERSTFLENGQDNPIG
  FLAYIMFWLVLTSSCPPYIAMSSIDDYKNRARSQLRISGLSPSAYWFGQALVDVSLYFLV
  FVFIYLMSYISNFEDMLLTIIHIIQIPCAVGYSFSLIFMTYVISFIFRKGRKNSGIWSFC
  FYVVTVFSVAGFAFSIFESDIPFIFTFLIPPATMIGCLFLSSHLLFSSLFSEERMDVQPF
  LVFLIPFLHFIIFLFTLRCLEWKFGKKSMRKDPFFRISPRSSDVCQNPEEPEGEDEDVQM
  ERVRTANALNSTNFDEKPVIIASCLRKEYAGKRKGCFSKRKNKIATRNVSFCVRKGEVLG
  LLGHNGAGKSTSIKVITGDTKPTAGQVLLKGSGGGDALEFLGYCPQENALWPNLTVRQHL
  EVYAAVKGLRKGDAEVAITRLVDALKLQDQLKSPVKTLSEGIKRKLCFVLSILGNPSVVL
  LDEPSTGMDPEGQQQMWQAIRATFRNTERGALLTTHYMAEAEAVCDRVAIMVSGRLRCIG
  SIQHLKSKFGKDYLLEMKVKNLAQVEPLHAEILRLFPQAARQERYSSLMVYKLPVEDVQP
  LAQAFFKLEKVKQSFDLEEYSLSQSTLEQVFLELSKEQELGDFEEDFDPSVKWKLLPQEE
  P
• Function: [Isoform 1]: Catalyzes ATP-dependent import of organic anions such as taurocholate and estrone sulfate. In vitro, also imports ochratoxin A. Also mediates cholesterol efflux independent of apolipoprotein, and plays a role in sphingomyelin production in oligodendrocytes ; [Isoform 3]: Catalyzes ATP-dependent efflux of cholesterol and taurocholate. Interaction with ABCA1 potentiates cholesterol efflux to lipid-free APOA1, which regulates high-density lipoprotein cholesterol levels.
• Tissue Specificity: Widely expressed with higher expression in heart, skeletal muscle and liver . Highly expressed in the superior frontal white matter and inferior temporal white matter .
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway: ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Taurocholic acid	DM2LZ8F	Phase 1/2	ABC-type organic anion transporter ABCA8 (ABCA8) affects the transport of Taurocholic acid.	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	ABC-type organic anion transporter ABCA8 (ABCA8) affects the transport of 3R14S-OCHRATOXIN A.	[13]
Aminohippuric acid	DMUN54G	Investigative	ABC-type organic anion transporter ABCA8 (ABCA8) affects the transport of Aminohippuric acid.	[13]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	ABC-type organic anion transporter ABCA8 (ABCA8) affects the transport of [3H]estrone-3-sulphate.	[13]
LTC4	DM702WR	Investigative	ABC-type organic anion transporter ABCA8 (ABCA8) affects the transport of LTC4.	[13]
[3H]estradiol-17beta-glucuronide	DM3KJ45	Investigative	ABC-type organic anion transporter ABCA8 (ABCA8) increases the uptake of [3H]estradiol-17beta-glucuronide.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of ABC-type organic anion transporter ABCA8 (ABCA8).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ABC-type organic anion transporter ABCA8 (ABCA8).	[12]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [8] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [9] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [10] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [13] Functional analysis of ABCA8, a new drug transporter. Biochem Biophys Res Commun. 2002 Oct 18;298(1):41-5.