Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT60WAAI)

• DOT Name: Solute carrier family 22 member 15 (SLC22A15)
• Synonyms: Fly-like putative transporter 1; Flipt 1
• Gene Name: SLC22A15
• Related Disease:
  Autism
  Colorectal carcinoma
  Epstein barr virus infection
  Colorectal neoplasm
• UniProt ID: S22AF_HUMAN
• Pfam ID: PF00083
• Sequence:
  MEVEEAFQAVGEMGIYQMYLCFLLAVLLQLYVATEAILIALVGATPSYHWDLAELLPNQS
  HGNQSAGEDQAFGDWLLTANGSEIHKHVHFSSSFTSIASEWFLIANRSYKVSAASSFFFS
  GVFVGVISFGQLSDRFGRKKVYLTGFALDILFAIANGFSPSYEFFAVTRFLVGMMNGGMS
  LVAFVLLNECVGTAYWALAGSIGGLFFAVGIAQYALLGYFIRSWRTLAILVNLQGTVVFL
  LSLFIPESPRWLYSQGRLSEAEEALYLIAKRNRKLKCTFSLTHPANRSCRETGSFLDLFR
  YRVLLGHTLILMFIWFVCSLVYYGLTLSAGDLGGSIYANLALSGLIEIPSYPLCIYLINQ
  KWFGRKRTLSAFLCLGGLACLIVMFLPEKKDTGVFAVVNSHSLSLLGKLTISAAFNIVYI
  YTSELYPTVIRNVGLGTCSMFSRVGGIIAPFIPSLKYVQWSLPFIVFGATGLTSGLLSLL
  LPETLNSPLLETFSDLQVYSYRRLGEEALSLQALDPQQCVDKESSLGSESEEEEEFYDAD
  EETQMIK
• Function: Organic zwitterion/cation transporter with apparent specificity for amino acids and their derivatives. Has low affinity for its substrates and may regulate their flux across the plasma membrane at high substrate concentrations. Bidirectionally transports carnitine and acetylcarnitine, possibly regulating their cytosolic abundance and further fatty acid catabolism via beta oxidation. Displays high transport activity toward zwitterionic substrates such as glycine betaine and diet-derived ergothioneine and carnosine. Can transport cations having an indole skeleton such as thiamine with lower efficiency. Does not transport agmatine. The transport mechanism, symport with sodium or facilitated diffusion allosterically regulated by sodium, remains to be elucidated (Probable).
• Tissue Specificity: Expressed at highest levels in kidney and brain. Expressed at high levels in skeletal muscle, heart, liver, placenta and white blood cells. Expressed at moderate levels in lung and spleen. Expressed at low levels in thymus, small intestine and colon. Expressed in several intestinal tumor cell lines.
• Reactome Pathway: Organic cation transport (R-HSA-549127)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[2]
Epstein barr virus infection	DISOO0WT	Strong	Genetic Variation	[3]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[2]

20 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 Solute carrier family 22 member 15 (SLC22A15).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Solute carrier family 22 member 15 (SLC22A15).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[15]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[16]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[17]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Solute carrier family 22 member 15 (SLC22A15).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Solute carrier family 22 member 15 (SLC22A15).	[21]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Solute carrier family 22 member 15 (SLC22A15).	[22]

References

• [1] Individual common variants exert weak effects on the risk for autism spectrum disorders.Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.
• [2] Genomic and epigenomic integration identifies a prognostic signature in colon cancer.Clin Cancer Res. 2011 Mar 15;17(6):1535-45. doi: 10.1158/1078-0432.CCR-10-2509. Epub 2011 Jan 28.
• [3] Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples.PLoS One. 2017 Jun 27;12(6):e0179446. doi: 10.1371/journal.pone.0179446. eCollection 2017.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] 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.
• [11] 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.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] 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.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [17] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] 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.
• [22] 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.