Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2PITLX)

• DOT Name: ATP-binding cassette sub-family D member 3 (ABCD3)
• Synonyms: EC 3.1.2.-; EC 7.6.2.-; 70 kDa peroxisomal membrane protein; PMP70
• Gene Name: ABCD3
• Related Disease: Congenital bile acid synthesis defect 5
• UniProt ID: ABCD3_HUMAN
• EC Number: 3.1.2.-; 7.6.2.-
• Pfam ID: PF06472 ; PF00005
• Sequence:
  MAAFSKYLTARNSSLAGAAFLLLCLLHKRRRALGLHGKKSGKPPLQNNEKEGKKERAVVD
  KVFFSRLIQILKIMVPRTFCKETGYLVLIAVMLVSRTYCDVWMIQNGTLIESGIIGRSRK
  DFKRYLLNFIAAMPLISLVNNFLKYGLNELKLCFRVRLTKYLYEEYLQAFTYYKMGNLDN
  RIANPDQLLTQDVEKFCNSVVDLYSNLSKPFLDIVLYIFKLTSAIGAQGPASMMAYLVVS
  GLFLTRLRRPIGKMTITEQKYEGEYRYVNSRLITNSEEIAFYNGNKREKQTVHSVFRKLV
  EHLHNFILFRFSMGFIDSIIAKYLATVVGYLVVSRPFLDLSHPRHLKSTHSELLEDYYQS
  GRMLLRMSQALGRIVLAGREMTRLAGFTARITELMQVLKDLNHGKYERTMVSQQEKGIEG
  VQVIPLIPGAGEIIIADNIIKFDHVPLATPNGDVLIRDLNFEVRSGANVLICGPNGCGKS
  SLFRVLGELWPLFGGRLTKPERGKLFYVPQRPYMTLGTLRDQVIYPDGREDQKRKGISDL
  VLKEYLDNVQLGHILEREGGWDSVQDWMDVLSGGEKQRMAMARLFYHKPQFAILDECTSA
  VSVDVEGYIYSHCRKVGITLFTVSHRKSLWKHHEYYLHMDGRGNYEFKQITEDTVEFGS
• Function: Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that catalyzes the transport of long-chain fatty acids (LCFA)-CoA, dicarboxylic acids-CoA, long-branched-chain fatty acids-CoA and bile acids from the cytosol to the peroxisome lumen for beta-oxydation. Has fatty acyl-CoA thioesterase and ATPase activities. Probably hydrolyzes fatty acyl-CoAs into free fatty acids prior to their ATP-dependent transport into peroxisomes. Thus, play a role in regulation of LCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation.
• KEGG Pathway:
  ABC transporters (hsa02010)
  Peroxisome (hsa04146)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOC GTPase cycle (R-HSA-9013106)
  Class I peroxisomal membrane protein import (R-HSA-9603798)
  ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital bile acid synthesis defect 5	DISNE17X	Limited	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	ATP-binding cassette sub-family D member 3 (ABCD3) affects the response to substance of Topotecan.	[21]

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 ATP-binding cassette sub-family D member 3 (ABCD3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[18]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[19]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of ATP-binding cassette sub-family D member 3 (ABCD3).	[20]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] 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.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Activation of autophagy triggers mitochondrial loss and changes acetylation profile relevant for mechanotransduction in bladder cancer cells. Arch Toxicol. 2023 Jan;97(1):217-233. doi: 10.1007/s00204-022-03375-2. Epub 2022 Oct 10.
• [20] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.