Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXWVV9O)

• DOT Name: Sodium/nucleoside cotransporter 1 (SLC28A1)
• Synonyms: Concentrative nucleoside transporter 1; CNT 1; hCNT1; Na(+)/nucleoside cotransporter 1; Sodium-coupled nucleoside transporter 1; Solute carrier family 28 member 1
• Gene Name: SLC28A1
• UniProt ID: S28A1_HUMAN
• Pfam ID: PF07670 ; PF07662 ; PF01773
• Sequence:
  MENDPSRRRESISLTPVAKGLENMGADFLESLEEGQLPRSDLSPAEIRSSWSEAAPKPFS
  RWRNLQPALRARSFCREHMQLFRWIGTGLLCTGLSAFLLVACLLDFQRALALFVLTCVVL
  TFLGHRLLKRLLGPKLRRFLKPQGHPRLLLWFKRGLALAAFLGLVLWLSLDTSQRPEQLV
  SFAGICVFVALLFACSKHHCAVSWRAVSWGLGLQFVLGLLVIRTEPGFIAFEWLGEQIRI
  FLSYTKAGSSFVFGEALVKDVFAFQVLPIIVFFSCVISVLYHVGLMQWVILKIAWLMQVT
  MGTTATETLSVAGNIFVSQTEAPLLIRPYLADMTLSEVHVVMTGGYATIAGSLLGAYISF
  GIDATSLIAASVMAAPCALALSKLVYPEVEESKFRREEGVKLTYGDAQNLIEAASTGAAI
  SVKVVANIAANLIAFLAVLDFINAALSWLGDMVDIQGLSFQLICSYILRPVAFLMGVAWE
  DCPVVAELLGIKLFLNEFVAYQDLSKYKQRRLAGAEEWVGDRKQWISVRAEVLTTFALCG
  FANFSSIGIMLGGLTSMVPQRKSDFSQIVLRALFTGACVSLVNACMAGILYMPRGAEVDC
  MSLLNTTLSSSSFEIYQCCREAFQSVNPEFSPEALDNCCRFYNHTICAQ
• Function: Sodium and pyrimidine nucleoside symporter of the plasma membrane that imports uridine, thymidine and cytidine into cells by coupling their transport to the transmembrane sodium electrochemical gradient. Also transports adenosine, an atypical substrate transported with high apparent affinity, but low maximum velocity. Therefore, exhibits the transport characteristics of the nucleoside transport system cit or N2 subtype (N2/cit). Involved in renal nucleoside (re)absorption.
• Tissue Specificity: Expressed in kidney.
• Reactome Pathway: Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (R-HSA-83936)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Sodium/nucleoside cotransporter 1 (SLC28A1) increases the response to substance of Decitabine.	[9]
Azacitidine	DMTA5OE	Approved	Sodium/nucleoside cotransporter 1 (SLC28A1) increases the response to substance of Azacitidine.	[9]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Zidovudine	DM4KI7O	Approved	Sodium/nucleoside cotransporter 1 (SLC28A1) affects the transport of Zidovudine.	[10]
Adenosine	DMM2NSK	Approved	Sodium/nucleoside cotransporter 1 (SLC28A1) affects the transport of Adenosine.	[10]
Uridine	DMQTREB	Approved	Sodium/nucleoside cotransporter 1 (SLC28A1) increases the transport of Uridine.	[11]
DEOXYCYTIDINE	DMYE5LJ	Approved	Sodium/nucleoside cotransporter 1 (SLC28A1) increases the transport of DEOXYCYTIDINE.	[11]
Cytidine	DMK0W8E	Investigative	Sodium/nucleoside cotransporter 1 (SLC28A1) increases the transport of Cytidine.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sodium/nucleoside cotransporter 1 (SLC28A1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium/nucleoside cotransporter 1 (SLC28A1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Sodium/nucleoside cotransporter 1 (SLC28A1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium/nucleoside cotransporter 1 (SLC28A1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium/nucleoside cotransporter 1 (SLC28A1).	[3]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Sodium/nucleoside cotransporter 1 (SLC28A1).	[4]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium/nucleoside cotransporter 1 (SLC28A1).	[5]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sodium/nucleoside cotransporter 1 (SLC28A1).	[8]

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] 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.
• [4] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] 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.
• [7] 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.
• [8] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [9] Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation. Mol Cancer Ther. 2009 Jan;8(1):225-31. doi: 10.1158/1535-7163.MCT-08-0743.
• [10] Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1). Am J Physiol. 1997 Feb;272(2 Pt 1):C707-14. doi: 10.1152/ajpcell.1997.272.2.C707.
• [11] Differential transport of cytosine-containing nucleosides by recombinant human concentrative nucleoside transporter protein hCNT1. Nucleosides Nucleotides Nucleic Acids. 2000 Jan-Feb;19(1-2):415-34. doi: 10.1080/15257770008033018.