Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOWP1CT)

• DOT Name: Thiamine transporter 2 (SLC19A3)
• Synonyms: ThTr-2; ThTr2; Solute carrier family 19 member 3
• Gene Name: SLC19A3
• Related Disease:
  Biotin-responsive basal ganglia disease
  Leigh syndrome
  Infantile spams-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome
  Obsolete Leigh syndrome with leukodystrophy
  Obsolete thiamine-responsive encephalopathy
• UniProt ID: S19A3_HUMAN
• Pfam ID: PF01770
• Sequence:
  MDCYRTSLSSSWIYPTVILCLFGFFSMMRPSEPFLIPYLSGPDKNLTSAEITNEIFPVWT
  YSYLVLLLPVFVLTDYVRYKPVIILQGISFIITWLLLLFGQGVKTMQVVEFFYGMVTAAE
  VAYYAYIYSVVSPEHYQRVSGYCRSVTLAAYTAGSVLAQLLVSLANMSYFYLNVISLASV
  SVAFLFSLFLPMPKKSMFFHAKPSREIKKSSSVNPVLEETHEGEAPGCEEQKPTSEILST
  SGKLNKGQLNSLKPSNVTVDVFVQWFQDLKECYSSKRLFYWSLWWAFATAGFNQVLNYVQ
  ILWDYKAPSQDSSIYNGAVEAIATFGGAVAAFAVGYVKVNWDLLGELALVVFSVVNAGSL
  FLMHYTANIWACYAGYLIFKSSYMLLITIAVFQIAVNLNVERYALVFGINTFIALVIQTI
  MTVIVVDQRGLNLPVSIQFLVYGSYFAVIAGIFLMRSMYITYSTKSQKDVQSPAPSENPD
  VSHPEEESNIIMSTKL
• Function: Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism. Has no folate transport activity. Mediates H(+)-dependent pyridoxine transport.
• Tissue Specificity: Widely expressed but most abundant in placenta, kidney and liver.
• KEGG Pathway: Vitamin digestion and absorption (hsa04977)
• Reactome Pathway: Vitamin B1 (thiamin) metabolism (R-HSA-196819)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Biotin-responsive basal ganglia disease	DISKPI9G	Definitive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
Infantile spams-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome	DISMDM8N	Supportive	Autosomal recessive	[3]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[4]
Obsolete thiamine-responsive encephalopathy	DISGZAFU	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Famotidine	DMRL3AB	Approved	Thiamine transporter 2 (SLC19A3) increases the uptake of Famotidine.	[21]

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 Thiamine transporter 2 (SLC19A3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Thiamine transporter 2 (SLC19A3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Thiamine transporter 2 (SLC19A3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Thiamine transporter 2 (SLC19A3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Thiamine transporter 2 (SLC19A3).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Thiamine transporter 2 (SLC19A3).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Thiamine transporter 2 (SLC19A3).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Thiamine transporter 2 (SLC19A3).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Thiamine transporter 2 (SLC19A3).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Thiamine transporter 2 (SLC19A3).	[13]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Thiamine transporter 2 (SLC19A3).	[14]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Thiamine transporter 2 (SLC19A3).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Thiamine transporter 2 (SLC19A3).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Thiamine transporter 2 (SLC19A3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Thiamine transporter 2 (SLC19A3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Thiamine transporter 2 (SLC19A3).	[19]
[3H]thiamine	DMSHW2E	Investigative	[3H]thiamine increases the expression of Thiamine transporter 2 (SLC19A3).	[20]

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 Thiamine transporter 2 (SLC19A3).	[17]

References

• [1] Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy. N Engl J Med. 2009 Apr 23;360(17):1792-4. doi: 10.1056/NEJMc0809100.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations. BMC Med Genet. 2010 Dec 22;11:171. doi: 10.1186/1471-2350-11-171.
• [4] Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain. 2013 Mar;136(Pt 3):882-90. doi: 10.1093/brain/awt013. Epub 2013 Feb 18.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] 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.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] 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.
• [14] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] 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.
• [20] Thiamin uptake by the human-derived renal epithelial (HEK-293) cells: cellular and molecular mechanisms. Am J Physiol Renal Physiol. 2006 Oct;291(4):F796-805. doi: 10.1152/ajprenal.00078.2006. Epub 2006 May 16.
• [21] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015 Dec 7;12(12):4301-10.