Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO3VD5E)

• DOT Name: Sodium-coupled neutral amino acid symporter 1 (SLC38A1)
• Synonyms: Amino acid transporter A1; N-system amino acid transporter 2; Solute carrier family 38 member 1; System A amino acid transporter 1; System N amino acid transporter 1
• Gene Name: SLC38A1
• UniProt ID: S38A1_HUMAN
• Pfam ID: PF01490
• Sequence:
  MMHFKSGLELTELQNMTVPEDDNISNDSNDFTEVENGQINSKFISDRESRRSLTNSHLEK
  KKCDEYIPGTTSLGMSVFNLSNAIMGSGILGLAFALANTGILLFLVLLTSVTLLSIYSIN
  LLLICSKETGCMVYEKLGEQVFGTTGKFVIFGATSLQNTGAMLSYLFIVKNELPSAIKFL
  MGKEETFSAWYVDGRVLVVIVTFGIILPLCLLKNLGYLGYTSGFSLSCMVFFLIVVIYKK
  FQIPCIVPELNSTISANSTNADTCTPKYVTFNSKTVYALPTIAFAFVCHPSVLPIYSELK
  DRSQKKMQMVSNISFFAMFVMYFLTAIFGYLTFYDNVQSDLLHKYQSKDDILILTVRLAV
  IVAVILTVPVLFFTVRSSLFELAKKTKFNLCRHTVVTCILLVVINLLVIFIPSMKDIFGV
  VGVTSANMLIFILPSSLYLKITDQDGDKGTQRIWAALFLGLGVLFSLVSIPLVIYDWACS
  SSSDEGH
• Function: Symporter that cotransports short-chain neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane. The transport is elctrogenic, pH dependent and driven by the Na(+) electrochemical gradient. Participates in the astroglia-derived glutamine transport into GABAergic interneurons for neurotransmitter GABA de novo synthesis. May also contributes to amino acid transport in placental trophoblasts. Also regulates synaptic plasticity.
• Tissue Specificity: Expressed in the cerebral cortex by pyramidal and GABAergic neurons, astrocytes and other non-neuronal cells (at protein level). Expressed in placenta, heart, lung, skeletal muscle, spleen, stomach and testis . Highly expressed in cytotrophoblast cells from term placenta .
• KEGG Pathway:
  Glutamatergic sy.pse (hsa04724)
  GABAergic sy.pse (hsa04727)
• Reactome Pathway:
  Amino acid transport across the plasma membrane (R-HSA-352230)
  Astrocytic Glutamate-Glutamine Uptake And Metabolism (R-HSA-210455)

Molecular Interaction Atlas (MIA) of This DOT

20 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 Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[15]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[21]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sodium-coupled neutral amino acid symporter 1 (SLC38A1).	[14]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [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] Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.
• [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] 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.
• [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] 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.
• [15] 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.
• [16] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [22] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.