Details of Drug Off-Target (DOT)

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

• DOT Name: Equilibrative nucleoside transporter 1 (SLC29A1)
• Synonyms: hENT1; Equilibrative nitrobenzylmercaptopurine riboside-sensitive nucleoside transporter; Equilibrative NBMPR-sensitive nucleoside transporter; es nucleoside transporter; Nucleoside transporter, es-type; Solute carrier family 29 member 1
• Gene Name: SLC29A1
• UniProt ID: S29A1_HUMAN
• PDB ID: 6OB6; 6OB7
• Pfam ID: PF01733
• Sequence:
  MTTSHQPQDRYKAVWLIFFMLGLGTLLPWNFFMTATQYFTNRLDMSQNVSLVTAELSKDA
  QASAAPAAPLPERNSLSAIFNNVMTLCAMLPLLLFTYLNSFLHQRIPQSVRILGSLVAIL
  LVFLITAILVKVQLDALPFFVITMIKIVLINSFGAILQGSLFGLAGLLPASYTAPIMSGQ
  GLAGFFASVAMICAIASGSELSESAFGYFITACAVIILTIICYLGLPRLEFYRYYQQLKL
  EGPGEQETKLDLISKGEEPRAGKEESGVSVSNSQPTNESHSIKAILKNISVLAFSVCFIF
  TITIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLTFNIFDWLGRSLTAVFMWPGKDSRW
  LPSLVLARLVFVPLLLLCNIKPRRYLTVVFEHDAWFIFFMAAFAFSNGYLASLCMCFGPK
  KVKPAEAETAGAIMAFFLCLGLALGAVFSFLFRAIV
• Function: Uniporter involved in the facilitative transport of nucleosides and nucleobases, and contributes to maintaining their cellular homeostasis. Functions as a Na(+)-independent transporter. Involved in the transport of nucleosides such as adenosine, guanosine, inosine, uridine, thymidine and cytidine. Also transports purine nucleobases (hypoxanthine, adenine, guanine) and pyrimidine nucleobases (thymine, uracil). Mediates basolateral nucleoside uptake into Sertoli cells, thereby regulating the transport of nucleosides in testis across the blood-testis barrier. Regulates inosine levels in brown adipocytes tissues (BAT) and extracellular inosine levels, which controls BAT-dependent energy expenditure.
• Tissue Specificity: Expressed in testis at the blood-testis barrier (at protein level) . Detected in erythrocytes (at protein level) . Expressed at relatively high levels in cerebral cortex, particularly the frontal and parietal lobes, and the thalamus and basal ganglia (at protein level) . In the midbrain expressed at moderate levels, whereas in the other areas of the brainstem, namely medulla and pons, cerebellum and the hippocampus expressed at lower amounts when compared to the other brain regions (at protein level) . Expressed in Langerhans cells and lymphocytes in the pancreas (at protein level) . Expressed in kidney, in polarized renal epithelial cells . Expressed in adipose tissues . Expressed in placenta . Expressed in small intestine .
• KEGG Pathway: Alcoholism (hsa05034)
• Reactome Pathway:
  Azathioprine ADME (R-HSA-9748787)
  Ribavirin ADME (R-HSA-9755088)
  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 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cytarabine	DMZD5QR	Approved	Equilibrative nucleoside transporter 1 (SLC29A1) decreases the response to substance of Cytarabine.	[28]
Gemcitabine	DMSE3I7	Approved	Equilibrative nucleoside transporter 1 (SLC29A1) increases the response to substance of Gemcitabine.	[29]
Vinorelbine	DMVXFYE	Approved	Equilibrative nucleoside transporter 1 (SLC29A1) affects the response to substance of Vinorelbine.	[31]
Fialuridine	DMCIGRB	Phase 2	Equilibrative nucleoside transporter 1 (SLC29A1) affects the response to substance of Fialuridine.	[33]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine	DMM2NSK	Approved	Equilibrative nucleoside transporter 1 (SLC29A1) increases the uptake of Adenosine.	[30]
Uridine	DMQTREB	Approved	Equilibrative nucleoside transporter 1 (SLC29A1) increases the uptake of Uridine.	[32]
Ribavirin	DMEYLH9	Phase 1 Trial	Equilibrative nucleoside transporter 1 (SLC29A1) increases the uptake of Ribavirin.	[34]

27 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 Equilibrative nucleoside transporter 1 (SLC29A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[13]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[15]
Dipyridamole	DMXY30O	Approved	Dipyridamole decreases the activity of Equilibrative nucleoside transporter 1 (SLC29A1).	[16]
UFT	DMX3O0D	Approved	UFT increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[17]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[19]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[23]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Equilibrative nucleoside transporter 1 (SLC29A1).	[8]

4 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 Equilibrative nucleoside transporter 1 (SLC29A1).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Equilibrative nucleoside transporter 1 (SLC29A1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Equilibrative nucleoside transporter 1 (SLC29A1).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Equilibrative nucleoside transporter 1 (SLC29A1).	[24]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
S6-nitrobenzyl mercaptopurine riboside	DMIKJNL	Investigative	S6-nitrobenzyl mercaptopurine riboside affects the binding of Equilibrative nucleoside transporter 1 (SLC29A1).	[27]

References

• [1] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Schedule-dependent therapeutic effects of gemcitabine combined with uracil-tegafur in a human pancreatic cancer xenograft model. Pancreas. 2006 Aug;33(2):142-7. doi: 10.1097/01.mpa.0000226882.48204.26.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [15] 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.
• [16] New role of the human equilibrative nucleoside transporter 1 (hENT1) in epithelial-to-mesenchymal transition in renal tubular cells. J Cell Physiol. 2012 Apr;227(4):1521-8. doi: 10.1002/jcp.22869.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [19] 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.
• [20] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] 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.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020 Jan 31;295(5):1271-1287. doi: 10.1074/jbc.RA119.011174. Epub 2019 Dec 5.
• [26] 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.
• [27] A semi-quantitative translational pharmacology analysis to understand the relationship between in vitro ENT1 inhibition and the clinical incidence of dyspnoea and bronchospasm. Toxicol Appl Pharmacol. 2017 Feb 15;317:41-50. doi: 10.1016/j.taap.2016.12.021. Epub 2016 Dec 29.
• [28] Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells. Cancer Res. 2008 Apr 1;68(7):2349-57. doi: 10.1158/0008-5472.CAN-07-5528.
• [29] Laser microdissection and primary cell cultures improve pharmacogenetic analysis in pancreatic adenocarcinoma. Lab Invest. 2008 Jul;88(7):773-84. doi: 10.1038/labinvest.2008.40. Epub 2008 May 19.
• [30] Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PLoS One. 2011 Jan 24;6(1):e16331. doi: 10.1371/journal.pone.0016331.
• [31] High expression of nucleoside transporter protein hENT1 in Reed-Sternberg cells is associated with treatment failure in relapsed/refractory Hodgkin lymphoma patients treated with gemcitabine, vinorelbine and liposomal doxorubicin - a CALGB 59804 correlative study. Leuk Lymphoma. 2008 Jun;49(6):1202-5. doi: 10.1080/10428190802094237.
• [32] Nucleoside transport in human colonic epithelial cell lines: evidence for two Na+-independent transport systems in T84 and Caco-2 cells. Biochim Biophys Acta. 1999 Jun 9;1419(1):15-22. doi: 10.1016/s0005-2736(99)00045-0.
• [33] Mechanisms of Chronic Fialuridine Hepatotoxicity as Revealed in Primary Human Hepatocyte Spheroids. Toxicol Sci. 2019 Oct 1;171(2):385-395. doi: 10.1093/toxsci/kfz195.
• [34] Characterization of ribavirin uptake systems in human hepatocytes. J Hepatol. 2010 Apr;52(4):486-92.