Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3B9M6W)

• DOT Name: Excitatory amino acid transporter 3 (SLC1A1)
• Synonyms: Excitatory amino-acid carrier 1; Neuronal and epithelial glutamate transporter; Sodium-dependent glutamate/aspartate transporter 3; Solute carrier family 1 member 1
• Gene Name: SLC1A1
• Related Disease:
  Dicarboxylic aminoaciduria
  Hot water reflex epilepsy
• UniProt ID: EAA3_HUMAN
• PDB ID: 6S3Q; 6X2L; 6X2Z; 6X3E; 6X3F; 7NSG; 8CTC; 8CTD; 8CUA; 8CUD; 8CUI; 8CUJ; 8CV2; 8CV3
• Pfam ID: PF00375
• Sequence:
  MGKPARKGCEWKRFLKNNWVLLSTVAAVVLGITTGVLVREHSNLSTLEKFYFAFPGEILM
  RMLKLIILPLIISSMITGVAALDSNVSGKIGLRAVVYYFCTTLIAVILGIVLVVSIKPGV
  TQKVGEIARTGSTPEVSTVDAMLDLIRNMFPENLVQACFQQYKTKREEVKPPSDPEMNMT
  EESFTAVMTTAISKNKTKEYKIVGMYSDGINVLGLIVFCLVFGLVIGKMGEKGQILVDFF
  NALSDATMKIVQIIMCYMPLGILFLIAGKIIEVEDWEIFRKLGLYMATVLTGLAIHSIVI
  LPLIYFIVVRKNPFRFAMGMAQALLTALMISSSSATLPVTFRCAEENNQVDKRITRFVLP
  VGATINMDGTALYEAVAAVFIAQLNDLDLGIGQIITISITATSASIGAAGVPQAGLVTMV
  IVLSAVGLPAEDVTLIIAVDWLLDRFRTMVNVLGDAFGTGIVEKLSKKELEQMDVSSEVN
  IVNPFALESTILDNEDSDTKKSYVNGGFAVDKSDTISFTQTSQF
• Function: Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate. Can also transport L-cysteine. Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion. Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport. Plays an important role in L-glutamate and L-aspartate reabsorption in renal tubuli. Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate. Contributes to glutathione biosynthesis and protection against oxidative stress via its role in L-glutamate and L-cysteine transport. Negatively regulated by ARL6IP5.
• Tissue Specificity: Expressed in all tissues tested including liver, muscle, testis, ovary, retinoblastoma cell line, neurons and brain (in which there was dense expression in substantia nigra, red nucleus, hippocampus and in cerebral cortical layers).
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Glutamatergic sy.pse (hsa04724)
  Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)
  Defective SLC1A1 is implicated in schizophrenia 18 (SCZD18) and dicarboxylic aminoaciduria (DCBXA) (R-HSA-5619067)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dicarboxylic aminoaciduria	DISVXLLV	Strong	Autosomal recessive	[1]
Hot water reflex epilepsy	DISC9DVS	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Excitatory amino acid transporter 3 (SLC1A1) affects the response to substance of Cisplatin.	[22]
Mitomycin	DMH0ZJE	Approved	Excitatory amino acid transporter 3 (SLC1A1) affects the response to substance of Mitomycin.	[23]

17 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 Excitatory amino acid transporter 3 (SLC1A1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Excitatory amino acid transporter 3 (SLC1A1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Excitatory amino acid transporter 3 (SLC1A1).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Excitatory amino acid transporter 3 (SLC1A1).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[16]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Excitatory amino acid transporter 3 (SLC1A1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Excitatory amino acid transporter 3 (SLC1A1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Excitatory amino acid transporter 3 (SLC1A1).	[20]

References

• [1] Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Invest. 2011 Jan;121(1):446-53.
• [2] Rare SLC1A1 variants in hot water epilepsy. Hum Genet. 2017 Jun;136(6):693-703. doi: 10.1007/s00439-017-1778-7. Epub 2017 Mar 21.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [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] Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertil Steril. 2008 Dec;90(6):2152-64.
• [8] 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.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [11] 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.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] 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.
• [16] 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.
• [17] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [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] Role of transporter genes in cisplatin resistance. In Vivo. 2008 May-Jun;22(3):279-83.
• [23] 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.