Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH5SB0M)

• DOT Name: Thiamine transporter 1 (SLC19A2)
• Synonyms: ThTr-1; ThTr1; Solute carrier family 19 member 2; Thiamine carrier 1; TC1
• Gene Name: SLC19A2
• Related Disease: Thiamine-responsive megaloblastic anemia syndrome
• UniProt ID: S19A2_HUMAN
• Pfam ID: PF01770
• Sequence:
  MDVPGPVSRRAAAAAATVLLRTARVRRECWFLPTALLCAYGFFASLRPSEPFLTPYLLGP
  DKNLTEREVFNEIYPVWTYSYLVLLFPVFLATDYLRYKPVVLLQGLSLIVTWFMLLYAQG
  LLAIQFLEFFYGIATATEIAYYSYIYSVVDLGMYQKVTSYCRSATLVGFTVGSVLGQILV
  SVAGWSLFSLNVISLTCVSVAFAVAWFLPMPQKSLFFHHIPSTCQRVNGIKVQNGGIVTD
  TPASNHLPGWEDIESKIPLNMEEPPVEEPEPKPDRLLVLKVLWNDFLMCYSSRPLLCWSV
  WWALSTCGYFQVVNYTQGLWEKVMPSRYAAIYNGGVEAVSTLLGAVAVFAVGYIKISWST
  WGEMTLSLFSLLIAAAVYIMDTVGNIWVCYASYVVFRIIYMLLITIATFQIAANLSMERY
  ALVFGVNTFIALALQTLLTLIVVDASGLGLEITTQFLIYASYFALIAVVFLASGAVSVMK
  KCRKLEDPQSSSQVTTS
• Function: High-affinity transporter for the intake of thiamine. Mediates H(+)-dependent pyridoxine transport.
• Tissue Specificity: Ubiquitous; most abundant in skeletal and cardiac muscle. Medium expression in placenta, heart, liver and kidney, low in lung.
• KEGG Pathway: Vitamin digestion and absorption (hsa04977)
• Reactome Pathway: Vitamin B1 (thiamin) metabolism (R-HSA-196819)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thiamine-responsive megaloblastic anemia syndrome	DISUODDF	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Thiamine transporter 1 (SLC19A2).	[2]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Thiamine transporter 1 (SLC19A2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Thiamine transporter 1 (SLC19A2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Thiamine transporter 1 (SLC19A2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Thiamine transporter 1 (SLC19A2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Thiamine transporter 1 (SLC19A2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Thiamine transporter 1 (SLC19A2).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Thiamine transporter 1 (SLC19A2).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Thiamine transporter 1 (SLC19A2).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Thiamine transporter 1 (SLC19A2).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Thiamine transporter 1 (SLC19A2).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Thiamine transporter 1 (SLC19A2).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Thiamine transporter 1 (SLC19A2).	[13]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Thiamine transporter 1 (SLC19A2).	[14]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Thiamine transporter 1 (SLC19A2).	[15]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Thiamine transporter 1 (SLC19A2).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Thiamine transporter 1 (SLC19A2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Thiamine transporter 1 (SLC19A2).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Thiamine transporter 1 (SLC19A2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Thiamine transporter 1 (SLC19A2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Thiamine transporter 1 (SLC19A2).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Thiamine transporter 1 (SLC19A2).	[22]
[3H]thiamine	DMSHW2E	Investigative	[3H]thiamine increases the expression of Thiamine transporter 1 (SLC19A2).	[23]
AM-630	DM7R605	Investigative	AM-630 decreases the expression of Thiamine transporter 1 (SLC19A2).	[24]

References

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• [2] 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.
• [3] 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.
• [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] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] 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.
• [11] 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.
• [12] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [15] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [16] 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.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] 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.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] 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.
• [24] Effect of cannabinoids upon the uptake of folic acid by BeWo cells. Pharmacology. 2009;83(3):170-6. doi: 10.1159/000192587. Epub 2009 Jan 15.