Details of Drug Off-Target (DOT)

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

• DOT Name: Equilibrative nucleoside transporter 4 (SLC29A4)
• Synonyms: hENT4; Plasma membrane monoamine transporter; PMAT; Solute carrier family 29 member 4
• Gene Name: SLC29A4
• UniProt ID: S29A4_HUMAN
• Pfam ID: PF01733
• Sequence:
  MGSVGSQRLEEPSVAGTPDPGVVMSFTFDSHQLEEAAEAAQGQGLRARGVPAFTDTTLDE
  PVPDDRYHAIYFAMLLAGVGFLLPYNSFITDVDYLHHKYPGTSIVFDMSLTYILVALAAV
  LLNNVLVERLTLHTRITAGYLLALGPLLFISICDVWLQLFSRDQAYAINLAAVGTVAFGC
  TVQQSSFYGYTGMLPKRYTQGVMTGESTAGVMISLSRILTKLLLPDERASTLIFFLVSVA
  LELLCFLLHLLVRRSRFVLFYTTRPRDSHRGRPGLGRGYGYRVHHDVVAGDVHFEHPAPA
  LAPNESPKDSPAHEVTGSGGAYMRFDVPRPRVQRSWPTFRALLLHRYVVARVIWADMLSI
  AVTYFITLCLFPGLESEIRHCILGEWLPILIMAVFNLSDFVGKILAALPVDWRGTHLLAC
  SCLRVVFIPLFILCVYPSGMPALRHPAWPCIFSLLMGISNGYFGSVPMILAAGKVSPKQR
  ELAGNTMTVSYMSGLTLGSAVAYCTYSLTRDAHGSCLHASTANGSILAGL
• Function: Electrogenic voltage-dependent transporter that mediates the transport of a variety of endogenous bioactive amines, cationic xenobiotics and drugs. Utilizes the physiologic inside-negative membrane potential as a driving force to facilitate cellular uptake of organic cations. Functions as a Na(+)- and Cl(-)-independent bidirectional transporter. Substrate transport is pH-dependent and enhanced under acidic condition, which is most likely the result of allosteric changes in the transporter structure. Implicated in monoamine neurotransmitters uptake such as serotonin, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, histamine and tyramine, thereby supporting a role in homeostatic regulation of aminergic neurotransmission in the central nervous system. Also responsible for the uptake of bioactive amines and drugs through the blood-cerebrospinal fluid (CSF) barrier, from the CSF into choroid plexus epithelial cells, thereby playing a significant role in the clearance of cationic neurotoxins, xenobiotics and metabolic waste in the brain. Involved in bidirectional transport of the purine nucleoside adenosine and plays a role in the regulation of extracellular adenosine concentrations in cardiac tissues, in particular during ischemia. May be involved in organic cation uptake from the tubular lumen into renal tubular cells, thereby contributing to organic cation reabsorption in the kidney. Also transports guanidine.
• Tissue Specificity: Mainly expressed in brain and skeletal muscle . In brain, expressed in cerebellum, cerebral cortex, medulla oblongata, occipital pole, frontal and temporal lobes putamen, spinal cord, substancia nigra, hippocampus, caudate nucleus, nucleus accumbens, pons and choroid plexus . Expressed in heart, in both cardiomyocytes and vascular endothelial cells . Also expressed in adrenal gland, small intestine, pancreas, kidney, liver, bone marrow, lymph node . Located in endometrial stroma, where the expression is high in the proliferative phase, decreases during the secretory phase, and is no longer detectable in the menstrual phase .
• 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 Regulation of Drug Effects of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Equilibrative nucleoside transporter 4 (SLC29A4) increases the abundance of Doxorubicin.	[12]
Dopamine	DMPGUCF	Approved	Equilibrative nucleoside transporter 4 (SLC29A4) increases the uptake of Dopamine.	[13]
Ergotidine	DM78IME	Approved	Equilibrative nucleoside transporter 4 (SLC29A4) increases the uptake of Ergotidine.	[13]
Epinephrine	DM3KJBC	Approved	Equilibrative nucleoside transporter 4 (SLC29A4) increases the uptake of Epinephrine.	[13]
Norepinephrine	DMOUC09	Approved	Equilibrative nucleoside transporter 4 (SLC29A4) increases the uptake of Norepinephrine.	[13]
Serotonin	DMOFCRY	Investigative	Equilibrative nucleoside transporter 4 (SLC29A4) increases the uptake of Serotonin.	[13]

2 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 Equilibrative nucleoside transporter 4 (SLC29A4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Equilibrative nucleoside transporter 4 (SLC29A4).	[10]

9 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 Equilibrative nucleoside transporter 4 (SLC29A4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[5]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Equilibrative nucleoside transporter 4 (SLC29A4).	[11]

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] Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol. 2014 Sep 1;279(2):163-72.
• [3] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [7] 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.
• [8] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [12] Inhibition of multiple uptake transporters in cardiomyocytes/mitochondria alleviates doxorubicin-induced cardiotoxicity. Chem Biol Interact. 2023 Sep 1;382:110627. doi: 10.1016/j.cbi.2023.110627. Epub 2023 Jul 13.
• [13] Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. Epub 2010 Sep 21.