Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8XXVO8)

• DOT Name: Large neutral amino acids transporter small subunit 2 (SLC7A8)
• Synonyms: L-type amino acid transporter 2; hLAT2; Solute carrier family 7 member 8
• Gene Name: SLC7A8
• UniProt ID: LAT2_HUMAN
• PDB ID: 7B00; 7CMH; 7CMI; 8A6L
• Pfam ID: PF13520
• Sequence:
  MEEGARHRNNTEKKHPGGGESDASPEAGSGGGGVALKKEIGLVSACGIIVGNIIGSGIFV
  SPKGVLENAGSVGLALIVWIVTGFITVVGALCYAELGVTIPKSGGDYSYVKDIFGGLAGF
  LRLWIAVLVIYPTNQAVIALTFSNYVLQPLFPTCFPPESGLRLLAAICLLLLTWVNCSSV
  RWATRVQDIFTAGKLLALALIIIMGIVQICKGEYFWLEPKNAFENFQEPDIGLVALAFLQ
  GSFAYGGWNFLNYVTEELVDPYKNLPRAIFISIPLVTFVYVFANVAYVTAMSPQELLASN
  AVAVTFGEKLLGVMAWIMPISVALSTFGGVNGSLFTSSRLFFAGAREGHLPSVLAMIHVK
  RCTPIPALLFTCISTLLMLVTSDMYTLINYVGFINYLFYGVTVAGQIVLRWKKPDIPRPI
  KINLLFPIIYLLFWAFLLVFSLWSEPVVCGIGLAIMLTGVPVYFLGVYWQHKPKCFSDFI
  ELLTLVSQKMCVVVYPEVERGSGTEEANEDMEEQQQPMYQPTPTKDKDVAGQPQP
• Function: Associates with SLC3A2 to form a functional heterodimeric complex that translocates small and large neutral amino acids with broad specificity and a stoichiometry of 1:1. Functions as amino acid antiporter mediating the influx of extracellular essential amino acids mainly in exchange with the efflux of highly concentrated intracellular amino acids. Has relatively symmetrical selectivities but strongly asymmetrical substrate affinities at both the intracellular and extracellular sides of the transporter. This asymmetry allows SLC7A8 to regulate intracellular amino acid pools (mM concentrations) by exchange with external amino acids (uM concentration range), equilibrating the relative concentrations of different amino acids across the plasma membrane instead of mediating their net uptake. May play an essential role in the reabsorption of neutral amino acids from the epithelial cells to the bloodstream in the kidney. Involved in the uptake of methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes, and hence plays a role in metal ion homeostasis and toxicity. Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the transmembrane. Imports the thyroid hormone diiodothyronine (T2) and to a smaller extent triiodothyronine (T3) but not rT 3 or thyroxine (T4). Mediates the uptake of L-DOPA. May participate in auditory function.
• Tissue Specificity: Strongest expression is observed in kidney and moderate expression in placenta and brain, followed by liver, prostate, testis, ovary, lymph node, thymus, spleen, skeletal muscle and heart. Also expressed in fetal liver as well as in the retinal pigment epithelial cell line ARPE-19 and the intestinal epithelial cell line Caco-2.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Amino acid transport across the plasma membrane (R-HSA-352230)
  Basigin interactions (R-HSA-210991)
• BioCyc Pathway: MetaCyc:ENSG00000092068-MONOMER

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
Cisplatin	DMRHGI9	Approved	Large neutral amino acids transporter small subunit 2 (SLC7A8) affects the response to substance of Cisplatin.	[21]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
L-methionine	DME8G1U	Investigative	Large neutral amino acids transporter small subunit 2 (SLC7A8) affects the import of L-methionine.	[19]
L-leucine	DMQHN7I	Investigative	Large neutral amino acids transporter small subunit 2 (SLC7A8) affects the import of L-leucine.	[19]

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 Large neutral amino acids transporter small subunit 2 (SLC7A8).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[9]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[13]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[18]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[19]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Large neutral amino acids transporter small subunit 2 (SLC7A8).	[16]

References

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• [2] 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.
• [3] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] 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.
• [6] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [10] 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.
• [11] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [12] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [13] 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.
• [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] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter. Int J Mol Sci. 2017 Aug 8;18(8):1730. doi: 10.3390/ijms18081730.
• [20] In vitro effects of lead on gene expression in neural stem cells and associations between up-regulated genes and cognitive scores in children. Environ Health Perspect. 2017 Apr;125(4):721-729.
• [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.