Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRDIR5M)

• DOT Name: Transient receptor potential cation channel subfamily A member 1 (TRPA1)
• Synonyms: Ankyrin-like with transmembrane domains protein 1; Transformation-sensitive protein p120; p120; Wasabi receptor
• Gene Name: TRPA1
• Related Disease: Familial episodic pain syndrome with predominantly upper body involvement
• UniProt ID: TRPA1_HUMAN
• PDB ID: 3J9P; 6HC8; 6PQO; 6PQP; 6PQQ; 6V9V; 6V9W; 6V9X; 6V9Y; 6WJ5; 6X2J; 7JUP; 7OR0; 7OR1
• Pfam ID: PF00023 ; PF12796 ; PF00520
• Sequence:
  MKRSLRKMWRPGEKKEPQGVVYEDVPDDTEDFKESLKVVFEGSAYGLQNFNKQKKLKRCD
  DMDTFFLHYAAAEGQIELMEKITRDSSLEVLHEMDDYGNTPLHCAVEKNQIESVKFLLSR
  GANPNLRNFNMMAPLHIAVQGMNNEVMKVLLEHRTIDVNLEGENGNTAVIIACTTNNSEA
  LQILLKKGAKPCKSNKWGCFPIHQAAFSGSKECMEIILRFGEEHGYSRQLHINFMNNGKA
  TPLHLAVQNGDLEMIKMCLDNGAQIDPVEKGRCTAIHFAATQGATEIVKLMISSYSGSVD
  IVNTTDGCHETMLHRASLFDHHELADYLISVGADINKIDSEGRSPLILATASASWNIVNL
  LLSKGAQVDIKDNFGRNFLHLTVQQPYGLKNLRPEFMQMQQIKELVMDEDNDGCTPLHYA
  CRQGGPGSVNNLLGFNVSIHSKSKDKKSPLHFAASYGRINTCQRLLQDISDTRLLNEGDL
  HGMTPLHLAAKNGHDKVVQLLLKKGALFLSDHNGWTALHHASMGGYTQTMKVILDTNLKC
  TDRLDEDGNTALHFAAREGHAKAVALLLSHNADIVLNKQQASFLHLALHNKRKEVVLTII
  RSKRWDECLKIFSHNSPGNKCPITEMIEYLPECMKVLLDFCMLHSTEDKSCRDYYIEYNF
  KYLQCPLEFTKKTPTQDVIYEPLTALNAMVQNNRIELLNHPVCKEYLLMKWLAYGFRAHM
  MNLGSYCLGLIPMTILVVNIKPGMAFNSTGIINETSDHSEILDTTNSYLIKTCMILVFLS
  SIFGYCKEAGQIFQQKRNYFMDISNVLEWIIYTTGIIFVLPLFVEIPAHLQWQCGAIAVY
  FYWMNFLLYLQRFENCGIFIVMLEVILKTLLRSTVVFIFLLLAFGLSFYILLNLQDPFSS
  PLLSIIQTFSMMLGDINYRESFLEPYLRNELAHPVLSFAQLVSFTIFVPIVLMNLLIGLA
  VGDIAEVQKHASLKRIAMQVELHTSLEKKLPLWFLRKVDQKSTIVYPNKPRSGGMLFHIF
  CFLFCTGEIRQEIPNADKSLEMEILKQKYRLKDLTFLLEKQHELIKLIIQKMEIISETED
  DDSHCSFQDRFKKEQMEQRNSRWNTVLRAVKAKTHHLEP
• Function: Receptor-activated non-selective cation channel involved in pain detection and possibly also in cold perception, oxygen concentration perception, cough, itch, and inner ear function. Shows 8-fold preference for divalent over monovalent cations. Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of irritants, such as allylthiocyanate (AITC) from mustard oil or wasabi, cinnamaldehyde, diallyl disulfide (DADS) from garlic, and acrolein, an irritant from tears gas and vehicle exhaust fumes. Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Is activated by a large variety of structurally unrelated electrophilic and non-electrophilic chemical compounds. Electrophilic ligands activate TRPA1 by interacting with critical N-terminal Cys residues in a covalent manner, whereas mechanisms of non-electrophilic ligands are not well determined. May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system.
• Tissue Specificity: Expressed at very low levels in fibroblasts.
• KEGG Pathway: Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial episodic pain syndrome with predominantly upper body involvement	DIS8X0WN	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mechlorethamine	DM0CVXA	Approved	Transient receptor potential cation channel subfamily A member 1 (TRPA1) increases the response to substance of Mechlorethamine.	[18]

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 Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Menadione	DMSJDTY	Approved	Menadione increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[3]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[4]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[3]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[5]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[7]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[10]
4-Methoxybenzaldehyde	DMN6GTZ	Patented	4-Methoxybenzaldehyde increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[3]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[11]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[12]
NAPQI	DM8F5LR	Investigative	NAPQI increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[13]
1,2-NAPHTHOQUINONE	DMYXELH	Investigative	1,2-NAPHTHOQUINONE increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[3]
carvacrol	DMINM2D	Investigative	carvacrol increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[14]
Go 6983	DMKVTZN	Investigative	Go 6983 decreases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[8]
Org-231295	DMTFGYH	Investigative	Org-231295 increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[15]
cannabinol	DMM6A7P	Investigative	cannabinol increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[16]
PD-169316	DM1Z3D7	Investigative	PD-169316 decreases the expression of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[8]
HC-030031	DMOY2AI	Investigative	HC-030031 decreases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[17]
NSC-115890	DMPLUHT	Investigative	NSC-115890 increases the activity of Transient receptor potential cation channel subfamily A member 1 (TRPA1).	[3]

References

• [1] A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron. 2010 Jun 10;66(5):671-80. doi: 10.1016/j.neuron.2010.04.030.
• [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] Electrophilic components of diesel exhaust particles (DEP) activate transient receptor potential ankyrin-1 (TRPA1): a probable mechanism of acute pulmonary toxicity for DEP. Chem Res Toxicol. 2011 Jun 20;24(6):950-9. doi: 10.1021/tx200123z. Epub 2011 May 25.
• [4] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [5] 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.
• [6] The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel. Toxicol Appl Pharmacol. 2017 Dec 1;336:55-65. doi: 10.1016/j.taap.2017.10.012. Epub 2017 Oct 18.
• [7] 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.
• [8] Mechanisms and Consequences of Variable TRPA1 Expression by Airway Epithelial Cells: Effects of TRPV1 Genotype and Environmental Agonists on Cellular Responses to Pollutants in Vitro and Asthma. Environ Health Perspect. 2023 Feb;131(2):27009. doi: 10.1289/EHP11076. Epub 2023 Feb 27.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] 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.
• [12] 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13519-24. doi: 10.1073/pnas.0705923104. Epub 2007 Aug 7.
• [13] Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J. 2010 Dec;24(12):4904-16. doi: 10.1096/fj.10-162438. Epub 2010 Aug 18.
• [14] Transient receptor potential ankyrin 1 activation enhances hapten sensitization in a T-helper type 2-driven fluorescein isothiocyanate-induced contact hypersensitivity mouse model. Toxicol Appl Pharmacol. 2012 Nov 1;264(3):370-6. doi: 10.1016/j.taap.2012.08.012. Epub 2012 Aug 23.
• [15] Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). Mol Pharmacol. 2007 May;71(5):1209-16. doi: 10.1124/mol.106.033621. Epub 2007 Feb 21.
• [16] Diverse TRPV1 responses to cannabinoids. Channels (Austin). 2019 Dec;13(1):172-191. doi: 10.1080/19336950.2019.1619436.
• [17] Activation of TRPV3 by Wood Smoke Particles and Roles in Pneumotoxicity. Chem Res Toxicol. 2018 May 21;31(5):291-301. doi: 10.1021/acs.chemrestox.7b00336. Epub 2018 Apr 30.
• [18] Activation of the human TRPA1 channel by different alkylating sulfur and nitrogen mustards and structurally related chemotherapeutic drugs. Toxicol Lett. 2023 Mar 1;376:51-59. doi: 10.1016/j.toxlet.2023.01.007. Epub 2023 Jan 21.