Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4B9D92)

• DOT Name: Cholesterol transporter ABCA5 (ABCA5)
• Synonyms: EC 7.6.2.-; ATP-binding cassette sub-family A member 5
• Gene Name: ABCA5
• Related Disease:
  Gingival fibromatosis-hypertrichosis syndrome
  Ventricular tachycardia, familial
• UniProt ID: ABCA5_HUMAN
• EC Number: 7.6.2.-
• Pfam ID: PF12698 ; PF00005
• Sequence:
  MSTAIREVGVWRQTRTLLLKNYLIKCRTKKSSVQEILFPLFFLFWLILISMMHPNKKYEE
  VPNIELNPMDKFTLSNLILGYTPVTNITSSIMQKVSTDHLPDVIITEEYTNEKEMLTSSL
  SKPSNFVGVVFKDSMSYELRFFPDMIPVSSIYMDSRAGCSKSCEAAQYWSSGFTVLQASI
  DAAIIQLKTNVSLWKELESTKAVIMGETAVVEIDTFPRGVILIYLVIAFSPFGYFLAIHI
  VAEKEKKIKEFLKIMGLHDTAFWLSWVLLYTSLIFLMSLLMAVIATASLLFPQSSSIVIF
  LLFFLYGLSSVFFALMLTPLFKKSKHVGIVEFFVTVAFGFIGLMIILIESFPKSLVWLFS
  PFCHCTFVIGIAQVMHLEDFNEGASFSNLTAGPYPLIITIIMLTLNSIFYVLLAVYLDQV
  IPGEFGLRRSSLYFLKPSYWSKSKRNYEELSEGNVNGNISFSEIIEPVSSEFVGKEAIRI
  SGIQKTYRKKGENVEALRNLSFDIYEGQITALLGHSGTGKSTLMNILCGLCPPSDGFASI
  YGHRVSEIDEMFEARKMIGICPQLDIHFDVLTVEENLSILASIKGIPANNIIQEVQKVLL
  DLDMQTIKDNQAKKLSGGQKRKLSLGIAVLGNPKILLLDEPTAGMDPCSRHIVWNLLKYR
  KANRVTVFSTHFMDEADILADRKAVISQGMLKCVGSSMFLKSKWGIGYRLSMYIDKYCAT
  ESLSSLVKQHIPGATLLQQNDQQLVYSLPFKDMDKFSGLFSALDSHSNLGVISYGVSMTT
  LEDVFLKLEVEAEIDQADYSVFTQQPLEEEMDSKSFDEMEQSLLILSETKAALVSTMSLW
  KQQMYTIAKFHFFTLKRESKSVRSVLLLLLIFFTVQIFMFLVHHSFKNAVVPIKLVPDLY
  FLKPGDKPHKYKTSLLLQNSADSDISDLISFFTSQNIMVTMINDSDYVSVAPHSAALNVM
  HSEKDYVFAAVFNSTMVYSLPILVNIISNYYLYHLNVTETIQIWSTPFFQEITDIVFKIE
  LYFQAALLGIIVTAMPPYFAMENAENHKIKAYTQLKLSGLLPSAYWIGQAVVDIPLFFII
  LILMLGSLLAFHYGLYFYTVKFLAVVFCLIGYVPSVILFTYIASFTFKKILNTKEFWSFI
  YSVAALACIAITEITFFMGYTIATILHYAFCIIIPIYPLLGCLISFIKISWKNVRKNVDT
  YNPWDRLSVAVISPYLQCVLWIFLLQYYEKKYGGRSIRKDPFFRNLSTKSKNRKLPEPPD
  NEDEDEDVKAERLKVKELMGCQCCEEKPSIMVSNLHKEYDDKKDFLLSRKVKKVATKYIS
  FCVKKGEILGLLGPNGAGKSTIINILVGDIEPTSGQVFLGDYSSETSEDDDSLKCMGYCP
  QINPLWPDTTLQEHFEIYGAVKGMSASDMKEVISRITHALDLKEHLQKTVKKLPAGIKRK
  LCFALSMLGNPQITLLDEPSTGMDPKAKQHMWRAIRTAFKNRKRAAILTTHYMEEAEAVC
  DRVAIMVSGQLRCIGTVQHLKSKFGKGYFLEIKLKDWIENLEVDRLQREIQYIFPNASRQ
  ESFSSILAYKIPKEDVQSLSQSFFKLEEAKHAFAIEEYSFSQATLEQVFVELTKEQEEED
  NSCGTLNSTLWWERTQEDRVVF
• Function: Cholesterol efflux transporter in macrophages that is responsible for APOAI/high-density lipoproteins (HDL) formation at the plasma membrane under high cholesterol levels and participates in reverse cholesterol transport. May play a role in the processing of autolysosomes.
• Tissue Specificity: Ubiquitously expressed. Highly expressed in testis, skeletal muscle, kidney, liver and placenta. Expressed in both the epithelial and mesenchymal compartments, present within the outer root sheath (ORS) of the hair follicle as well as dermal sheath . Expressed in multiple regions of the brain, including the hippocampus, superior frontal and inferior temporal cortices . Strongly expressed in neurons and moderately in microglia, with only weak expression in astrocytes and oligodendrocytes .
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway: ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gingival fibromatosis-hypertrichosis syndrome	DISDYHGH	Supportive	Autosomal dominant	[1]
Ventricular tachycardia, familial	DISYG7IE	Limited	Unknown	[2]

19 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 Cholesterol transporter ABCA5 (ABCA5).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[11]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[10]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[15]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Cholesterol transporter ABCA5 (ABCA5).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[17]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[18]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Cholesterol transporter ABCA5 (ABCA5).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cholesterol transporter ABCA5 (ABCA5).	[8]

References

• [1] Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth. PLoS Genet. 2014 May 15;10(5):e1004333.
• [2] Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia. Pediatr Cardiol. 2020 Dec;41(8):1783-1794. doi: 10.1007/s00246-020-02446-4. Epub 2020 Sep 16.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] Expression of copper-responsive genes in HepG2 cells. Mol Cell Biochem. 2005 Nov;279(1-2):141-7.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Evaluation of drug transporters' significance for multidrug resistance in head and neck squamous cell carcinoma. Head Neck. 2011 Jul;33(7):959-68. doi: 10.1002/hed.21559. Epub 2010 Aug 24.
• [12] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [19] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.