Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9CIHQ5)

• DOT Name: Thromboxane A2 receptor (TBXA2R)
• Synonyms: TXA2-R; Prostanoid TP receptor
• Gene Name: TBXA2R
• Related Disease:
  Obsolete bleeding diathesis due to thromboxane synthesis deficiency
  Qualitative platelet defect
  Schizophrenia
• UniProt ID: TA2R_HUMAN
• Pfam ID: PF00001
• Sequence:
  MWPNGSSLGPCFRPTNITLEERRLIASPWFAASFCVVGLASNLLALSVLAGARQGGSHTR
  SSFLTFLCGLVLTDFLGLLVTGTIVVSQHAALFEWHAVDPGCRLCRFMGVVMIFFGLSPL
  LLGAAMASERYLGITRPFSRPAVASQRRAWATVGLVWAAALALGLLPLLGVGRYTVQYPG
  SWCFLTLGAESGDVAFGLLFSMLGGLSVGLSFLLNTVSVATLCHVYHGQEAAQQRPRDSE
  VEMMAQLLGIMVVASVCWLPLLVFIAQTVLRNPPAMSPAGQLSRTTEKELLIYLRVATWN
  QILDPWVYILFRRAVLRRLQPRLSTRPRSLSLQPQLTQRSGLQ
• Function: Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C; [Isoform 1]: Activates adenylyl cyclase; [Isoform 2]: Inhibits adenylyl cyclase.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Platelet activation (hsa04611)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Prostanoid ligand receptors (R-HSA-391908)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete bleeding diathesis due to thromboxane synthesis deficiency	DISBO2EN	Moderate	Autosomal dominant	[1]
Qualitative platelet defect	DISNG54P	Moderate	Autosomal dominant	[2]
Schizophrenia	DISSRV2N	No Known	Unknown	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Thromboxane A2 receptor (TBXA2R) decreases the response to substance of Aspirin.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Thromboxane A2 receptor (TBXA2R).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Thromboxane A2 receptor (TBXA2R).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Thromboxane A2 receptor (TBXA2R).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thromboxane A2 receptor (TBXA2R).	[5]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Thromboxane A2 receptor (TBXA2R).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Thromboxane A2 receptor (TBXA2R).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Thromboxane A2 receptor (TBXA2R).	[8]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Thromboxane A2 receptor (TBXA2R).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Thromboxane A2 receptor (TBXA2R).	[11]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) decreases the expression of Thromboxane A2 receptor (TBXA2R).	[7]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014 Feb 13;506(7487):179-84. doi: 10.1038/nature12929. Epub 2014 Jan 22.
• [4] 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.
• [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] 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] Synthetic peroxisome proliferator-activated receptor gamma agonists rosiglitazone and troglitazone suppress transcription by promoter 3 of the human thromboxane A2 receptor gene in human erythroleukemia cells. Biochem Pharmacol. 2006 Apr 28;71(9):1308-23. doi: 10.1016/j.bcp.2006.01.011. Epub 2006 Feb 23.
• [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] 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.
• [10] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [12] Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity. Pharmacogenomics J. 2007 Dec;7(6):395-403. doi: 10.1038/sj.tpj.6500435. Epub 2007 Jan 23.