Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR2ZVA8)

• DOT Name: High affinity cationic amino acid transporter 1 (SLC7A1)
• Synonyms: CAT-1; CAT1; Ecotropic retroviral leukemia receptor homolog; Ecotropic retrovirus receptor homolog; Solute carrier family 7 member 1; System Y+ basic amino acid transporter
• Gene Name: SLC7A1
• UniProt ID: CTR1_HUMAN
• Pfam ID: PF13520 ; PF13906
• Sequence:
  MGCKVLLNIGQQMLRRKVVDCSREETRLSRCLNTFDLVALGVGSTLGAGVYVLAGAVARE
  NAGPAIVISFLIAALASVLAGLCYGEFGARVPKTGSAYLYSYVTVGELWAFITGWNLILS
  YIIGTSSVARAWSATFDELIGRPIGEFSRTHMTLNAPGVLAENPDIFAVIIILILTGLLT
  LGVKESAMVNKIFTCINVLVLGFIMVSGFVKGSVKNWQLTEEDFGNTSGRLCLNNDTKEG
  KPGVGGFMPFGFSGVLSGAATCFYAFVGFDCIATTGEEVKNPQKAIPVGIVASLLICFIA
  YFGVSAALTLMMPYFCLDNNSPLPDAFKHVGWEGAKYAVAVGSLCALSASLLGSMFPMPR
  VIYAMAEDGLLFKFLANVNDRTKTPIIATLASGAVAAVMAFLFDLKDLVDLMSIGTLLAY
  SLVAACVLVLRYQPEQPNLVYQMASTSDELDPADQNELASTNDSQLGFLPEAEMFSLKTI
  LSPKNMEPSKISGLIVNISTSLIAVLIITFCIVTVLGREALTKGALWAVFLLAGSALLCA
  VVTGVIWRQPESKTKLSFKVPFLPVLPILSIFVNVYLMMQLDQGTWVRFAVWMLIGFIIY
  FGYGLWHSEEASLDADQARTPDGNLDQCK
• Function: High-affinity, low capacity permease involved in the transport of the cationic amino acids (arginine, lysine and ornithine) in non-hepatic tissues.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: MicroR.s in cancer (hsa05206)
• Reactome Pathway: Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	High affinity cationic amino acid transporter 1 (SLC7A1) increases the Reticuloendothelial disorders NEC ADR of Progesterone.	[25]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	High affinity cationic amino acid transporter 1 (SLC7A1) affects the uptake of 3-iodothyronamine.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of High affinity cationic amino acid transporter 1 (SLC7A1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of High affinity cationic amino acid transporter 1 (SLC7A1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of High affinity cationic amino acid transporter 1 (SLC7A1).	[22]

24 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[11]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[12]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[13]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[12]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[14]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[14]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[16]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of High affinity cationic amino acid transporter 1 (SLC7A1).	[24]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [4] 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.
• [5] 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.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [13] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [14] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [15] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] 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.
• [23] 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.
• [24] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [25] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [26] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.