Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFOX70W)

• DOT Name: Thiopurine S-methyltransferase (TPMT)
• Synonyms: EC 2.1.1.67; Thiopurine methyltransferase
• Gene Name: TPMT
• UniProt ID: TPMT_HUMAN
• PDB ID: 2BZG; 2H11
• EC Number: 2.1.1.67
• Pfam ID: PF05724
• Sequence:
  MDGTRTSLDIEEYSDTEVQKNQVLTLEEWQDKWVNGKTAFHQEQGHQLLKKHLDTFLKGK
  SGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIQEFFTEQNLSYSEEPITEIPGTKV
  FKSSSGNISLYCCSIFDLPRTNIGKFDMIWDRGALVAINPGDRKCYADTMFSLLGKKFQY
  LLCVLSYDPTKHPGPPFYVPHAEIERLFGKICNIRCLEKVDAFEERHKSWGIDCLFEKLY
  LLTEK
• Function: Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S-adenosyl-L-methionine as the methyl donor. TPMT activity modulates the cytotoxic effects of thiopurine prodrugs. A natural substrate for this enzyme has yet to be identified.
• KEGG Pathway: Drug metabolism - other enzymes (hsa00983)
• Reactome Pathway:
  Defective TPMT causes TPMT deficiency (R-HSA-5578995)
  Azathioprine ADME (R-HSA-9748787)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS06327-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Azathioprine	DMMZSXQ	Approved	Thiopurine S-methyltransferase (TPMT) increases the Drug toxicity ADR of Azathioprine.	[19]
Mercaptopurine	DMTM2IK	Approved	Thiopurine S-methyltransferase (TPMT) affects the response to substance of Mercaptopurine.	[20]
Thioguanine	DM7NKEV	Approved	Thiopurine S-methyltransferase (TPMT) increases the Bone marrow toxicity ADR of Thioguanine.	[21]

19 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 Thiopurine S-methyltransferase (TPMT).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Thiopurine S-methyltransferase (TPMT).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Thiopurine S-methyltransferase (TPMT).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Thiopurine S-methyltransferase (TPMT).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thiopurine S-methyltransferase (TPMT).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Thiopurine S-methyltransferase (TPMT).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Thiopurine S-methyltransferase (TPMT).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Thiopurine S-methyltransferase (TPMT).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Thiopurine S-methyltransferase (TPMT).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Thiopurine S-methyltransferase (TPMT).	[11]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Thiopurine S-methyltransferase (TPMT).	[12]
Furosemide	DMMQ8ZG	Approved	Furosemide decreases the activity of Thiopurine S-methyltransferase (TPMT).	[13]
Bendroflumethiazide	DM7EVLC	Approved	Bendroflumethiazide decreases the activity of Thiopurine S-methyltransferase (TPMT).	[13]
Trichlormethiazide	DMHAQCO	Approved	Trichlormethiazide decreases the activity of Thiopurine S-methyltransferase (TPMT).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Thiopurine S-methyltransferase (TPMT).	[14]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Thiopurine S-methyltransferase (TPMT).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Thiopurine S-methyltransferase (TPMT).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Thiopurine S-methyltransferase (TPMT).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Thiopurine S-methyltransferase (TPMT).	[18]

1 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 Thiopurine S-methyltransferase (TPMT).	[6]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] Human drug metabolism genes in parathion-and estrogen-treated breast cells. Int J Mol Med. 2007 Dec;20(6):875-81.
• [5] 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.
• [6] 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.
• [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] 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.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [11] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [12] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [13] Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide. Eur J Clin Pharmacol. 1996;49(5):393-6.
• [14] 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.
• [15] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [16] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. Hum Mol Genet. 2012 Nov 1;21(21):4793-804.
• [20] Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. J Gastroenterol. 2003;38(8):740-6. doi: 10.1007/s00535-003-1139-2.
• [21] 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.