Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY5JFM1)

• DOT Name: Thymidine kinase, cytosolic (TK1)
• Synonyms: EC 2.7.1.21
• Gene Name: TK1
• UniProt ID: KITH_HUMAN
• PDB ID: 1W4R; 1XBT; 2ORV; 2WVJ
• EC Number: 2.7.1.21
• Pfam ID: PF00265
• Sequence:
  MSCINLPTVLPGSPSKTRGQIQVILGPMFSGKSTELMRRVRRFQIAQYKCLVIKYAKDTR
  YSSSFCTHDRNTMEALPACLLRDVAQEALGVAVIGIDEGQFFPDIVEFCEAMANAGKTVI
  VAALDGTFQRKPFGAILNLVPLAESVVKLTAVCMECFREAAYTKRLGTEKEVEVIGGADK
  YHSVCRLCYFKKASGQPAGPDNKENCPVPGKPGEAVAARKLFAPQQILQCSPAN
• Function: Cell-cycle-regulated enzyme of importance in nucleotide metabolism. Catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. Transcriptional regulation limits expression to the S phase of the cell cycle and transient expression coincides with the oscillation in the intracellular dTTP concentration (Probable). Also important for the activation of anticancer and antiviral nucleoside analog prodrugs such as 1-b-d-arabinofuranosylcytosine (AraC) and 3c-azido-3c-deoxythymidine (AZT).
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Pyrimidine salvage (R-HSA-73614)
  G1/S-Specific Transcription (R-HSA-69205)
• BioCyc Pathway: MetaCyc:HS09657-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Thymidine kinase, cytosolic (TK1) increases the Apoptosis ADR of Methotrexate.	[43]

47 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 Thymidine kinase, cytosolic (TK1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Thymidine kinase, cytosolic (TK1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Thymidine kinase, cytosolic (TK1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Thymidine kinase, cytosolic (TK1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Thymidine kinase, cytosolic (TK1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Thymidine kinase, cytosolic (TK1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Thymidine kinase, cytosolic (TK1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thymidine kinase, cytosolic (TK1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Thymidine kinase, cytosolic (TK1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Thymidine kinase, cytosolic (TK1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Thymidine kinase, cytosolic (TK1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Thymidine kinase, cytosolic (TK1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Thymidine kinase, cytosolic (TK1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Thymidine kinase, cytosolic (TK1).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Thymidine kinase, cytosolic (TK1).	[14]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Thymidine kinase, cytosolic (TK1).	[15]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of Thymidine kinase, cytosolic (TK1).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Thymidine kinase, cytosolic (TK1).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Thymidine kinase, cytosolic (TK1).	[17]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Thymidine kinase, cytosolic (TK1).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Thymidine kinase, cytosolic (TK1).	[19]
Ethanol	DMDRQZU	Approved	Ethanol decreases the activity of Thymidine kinase, cytosolic (TK1).	[20]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Thymidine kinase, cytosolic (TK1).	[21]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Thymidine kinase, cytosolic (TK1).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Thymidine kinase, cytosolic (TK1).	[22]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Thymidine kinase, cytosolic (TK1).	[23]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the mutagenesis of Thymidine kinase, cytosolic (TK1).	[24]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Thymidine kinase, cytosolic (TK1).	[25]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the mutagenesis of Thymidine kinase, cytosolic (TK1).	[26]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Thymidine kinase, cytosolic (TK1).	[28]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of Thymidine kinase, cytosolic (TK1).	[29]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the mutagenesis of Thymidine kinase, cytosolic (TK1).	[30]
Zalcitabine	DMH7MUV	Approved	Zalcitabine decreases the expression of Thymidine kinase, cytosolic (TK1).	[31]
Floxuridine	DM04LR2	Approved	Floxuridine increases the expression of Thymidine kinase, cytosolic (TK1).	[32]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Thymidine kinase, cytosolic (TK1).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Thymidine kinase, cytosolic (TK1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Thymidine kinase, cytosolic (TK1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Thymidine kinase, cytosolic (TK1).	[34]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Thymidine kinase, cytosolic (TK1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Thymidine kinase, cytosolic (TK1).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Thymidine kinase, cytosolic (TK1).	[37]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Thymidine kinase, cytosolic (TK1).	[38]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Thymidine kinase, cytosolic (TK1).	[39]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the mutagenesis of Thymidine kinase, cytosolic (TK1).	[40]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Thymidine kinase, cytosolic (TK1).	[41]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Thymidine kinase, cytosolic (TK1).	[42]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Thymidine kinase, cytosolic (TK1).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Zidovudine	DM4KI7O	Approved	Zidovudine increases the methylation of Thymidine kinase, cytosolic (TK1).	[27]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] 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.
• [10] E2F1 downregulation by arsenic trioxide in lung adenocarcinoma. Int J Oncol. 2014 Nov;45(5):2033-43. doi: 10.3892/ijo.2014.2609. Epub 2014 Aug 19.
• [11] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [14] 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.
• [15] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [16] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [17] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] Ethanol decreases the efficiency of phosphorylation of thymidine kinase in a human T-lymphocytic cell line. Alcohol Clin Exp Res. 2002 Mar;26(3):295-302.
• [21] Arabinosylcytosine downregulates thymidine kinase and induces cross-resistance to zidovudine in T-lymphoid cells. Biochem Biophys Res Commun. 2003 Aug 1;307(3):564-8. doi: 10.1016/s0006-291x(03)01232-4.
• [22] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [23] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [24] DNA polymerase kappa protects human cells against MMC-induced genotoxicity through error-free translesion DNA synthesis. Genes Environ. 2017 Jan 7;39:6. doi: 10.1186/s41021-016-0067-3. eCollection 2017.
• [25] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [26] Development of an integrated assay in human TK6 cells to permit comprehensive genotoxicity analysis in vitro. Mutat Res Genet Toxicol Environ Mutagen. 2020 Jan;849:503129. doi: 10.1016/j.mrgentox.2019.503129. Epub 2019 Dec 27.
• [27] AZT-induced hypermethylation of human thymidine kinase gene in the absence of total DNA hypermethylation. FEBS Lett. 1996 Nov 4;396(2-3):323-6. doi: 10.1016/0014-5793(96)01124-6.
• [28] Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38.
• [29] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [30] Delivery method, target gene structure, and growth properties of target cells impact mutagenic responses to reactive nitrogen and oxygen species. Chem Res Toxicol. 2012 Apr 16;25(4):873-83. doi: 10.1021/tx2004882. Epub 2012 Feb 21.
• [31] 2', 3'-Dideoxycytidine represses thymidine kinases 1 and 2 expression in T-lymphoid cells. Life Sci. 2004 Jan 2;74(7):835-42. doi: 10.1016/j.lfs.2003.07.023.
• [32] Fluorodeoxyuridine modulates cellular expression of the DNA base excision repair enzyme uracil-DNA glycosylase. Cancer Res. 2006 Sep 1;66(17):8829-37. doi: 10.1158/0008-5472.CAN-06-0540.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] 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.
• [35] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [36] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [37] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.
• [38] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [39] Geraniol, a component of plant essential oils, modulates DNA synthesis and potentiates 5-fluorouracil efficacy on human colon tumor xenografts. Cancer Lett. 2004 Nov 8;215(1):53-9.
• [40] Synergistic and Antagonistic Mutation Responses of Human MCL-5 Cells to Mixtures of Benzo[a]pyrene and 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine: Dose-Related Variation in the Joint Effects of Common Dietary Carcinogens. Environ Health Perspect. 2016 Jan;124(1):88-96. doi: 10.1289/ehp.1409557. Epub 2015 Jun 19.
• [41] Combined cytotoxicity of phthalate esters on HepG2 cells: A comprehensive analysis of transcriptomics and metabolomics. Food Chem Toxicol. 2023 Oct;180:114034. doi: 10.1016/j.fct.2023.114034. Epub 2023 Sep 12.
• [42] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.
• [43] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.