Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR60ZLA)

• DOT Name: Equilibrative nucleobase transporter 1 (SLC43A3)
• Synonyms: Protein FOAP-13; Solute carrier family 43 member 3
• Gene Name: SLC43A3
• UniProt ID: S43A3_HUMAN
• Sequence:
  MAGQGLPLHVATLLTGLLECLGFAGVLFGWPSLVFVFKNEDYFKDLCGPDAGPIGNATGQ
  ADCKAQDERFSLIFTLGSFMNNFMTFPTGYIFDRFKTTVARLIAIFFYTTATLIIAFTSA
  GSAVLLFLAMPMLTIGGILFLITNLQIGNLFGQHRSTIITLYNGAFDSSSAVFLIIKLLY
  EKGISLRASFIFISVCSTWHVARTFLLMPRGHIPYPLPPNYSYGLCPGNGTTKEEKETAE
  HENRELQSKEFLSAKEETPGAGQKQELRSFWSYAFSRRFAWHLVWLSVIQLWHYLFIGTL
  NSLLTNMAGGDMARVSTYTNAFAFTQFGVLCAPWNGLLMDRLKQKYQKEARKTGSSTLAV
  ALCSTVPSLALTSLLCLGFALCASVPILPLQYLTFILQVISRSFLYGSNAAFLTLAFPSE
  HFGKLFGLVMALSAVVSLLQFPIFTLIKGSLQNDPFYVNVMFMLAILLTFFHPFLVYREC
  RTWKESPSAIA
• Function: Sodium-independent purine-selective nucleobase transporter which mediates the equilibrative transport of extracellular purine nucleobases such as adenine, guanine and hypoxanthine. May regulate fatty acid (FA) transport in adipocytes, acting as a positive regulator of FA efflux and as a negative regulator of FA uptake; [Isoform 1]: Sodium-independent purine-selective nucleobase transporter which mediates the equilibrative transport of extracellular purine nucleobase adenine. Mediates the influx and efflux of the purine nucleobase analog drug 6-mercaptopurine across the membrane ; [Isoform 2]: Sodium-independent purine-selective nucleobase transporter which mediates the equilibrative transport of extracellular purine nucleobase adenine. Mediates the influx and efflux of the purine nucleobase analog drug 6-mercaptopurine across the membrane.
• Tissue Specificity: Widely expressed with highest levels in the liver and lung, followed by the pancreas . Highly expressed in macrophages (Ref.1).

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Equilibrative nucleobase transporter 1 (SLC43A3) affects the uptake of 3-iodothyronamine.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[9]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[11]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[12]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Equilibrative nucleobase transporter 1 (SLC43A3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Equilibrative nucleobase transporter 1 (SLC43A3).	[14]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [4] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [12] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.