Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHHDR03)

• DOT Name: Transient receptor potential cation channel subfamily V member 1 (TRPV1)
• Synonyms: TrpV1; Capsaicin receptor; Osm-9-like TRP channel 1; OTRPC1; Vanilloid receptor 1
• Gene Name: TRPV1
• UniProt ID: TRPV1_HUMAN
• PDB ID: 6L93; 8GF8; 8GF9; 8GFA
• Pfam ID: PF00023 ; PF12796 ; PF00520
• Sequence:
  MKKWSSTDLGAAADPLQKDTCPDPLDGDPNSRPPPAKPQLSTAKSRTRLFGKGDSEEAFP
  VDCPHEEGELDSCPTITVSPVITIQRPGDGPTGARLLSQDSVAASTEKTLRLYDRRSIFE
  AVAQNNCQDLESLLLFLQKSKKHLTDNEFKDPETGKTCLLKAMLNLHDGQNTTIPLLLEI
  ARQTDSLKELVNASYTDSYYKGQTALHIAIERRNMALVTLLVENGADVQAAAHGDFFKKT
  KGRPGFYFGELPLSLAACTNQLGIVKFLLQNSWQTADISARDSVGNTVLHALVEVADNTA
  DNTKFVTSMYNEILMLGAKLHPTLKLEELTNKKGMTPLALAAGTGKIGVLAYILQREIQE
  PECRHLSRKFTEWAYGPVHSSLYDLSCIDTCEKNSVLEVIAYSSSETPNRHDMLLVEPLN
  RLLQDKWDRFVKRIFYFNFLVYCLYMIIFTMAAYYRPVDGLPPFKMEKTGDYFRVTGEIL
  SVLGGVYFFFRGIQYFLQRRPSMKTLFVDSYSEMLFFLQSLFMLATVVLYFSHLKEYVAS
  MVFSLALGWTNMLYYTRGFQQMGIYAVMIEKMILRDLCRFMFVYIVFLFGFSTAVVTLIE
  DGKNDSLPSESTSHRWRGPACRPPDSSYNSLYSTCLELFKFTIGMGDLEFTENYDFKAVF
  IILLLAYVILTYILLLNMLIALMGETVNKIAQESKNIWKLQRAITILDTEKSFLKCMRKA
  FRSGKLLQVGYTPDGKDDYRWCFRVDEVNWTTWNTNVGIINEDPGNCEGVKRTLSFSLRS
  SRVSGRHWKNFALVPLLREASARDRQSAQPEEVYLRQFSGSLKPEDAEVFKSPAASGEK
• Function: Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis.
• Tissue Specificity: Widely expressed at low levels. Expression is elevated in dorsal root ganglia. In skin, expressed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands (at protein level).
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
2-arachidonoylglycerol	DMM0KOJ	Investigative	Transient receptor potential cation channel subfamily V member 1 (TRPV1) affects the response to substance of 2-arachidonoylglycerol.	[26]
ALLICIN	DMSOJ6H	Investigative	Transient receptor potential cation channel subfamily V member 1 (TRPV1) increases the response to substance of ALLICIN.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[8]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[10]
Menthol	DMG2KW7	Approved	Menthol increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[11]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[12]
Lidocaine	DML4ZOT	Approved	Lidocaine increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[17]
Citrate	DM37NYK	Preclinical	Citrate increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[21]
Anandamide	DMCKH3P	Investigative	Anandamide increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[22]
NADA	DM3ORGM	Investigative	NADA increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[23]
Go 6983	DMKVTZN	Investigative	Go 6983 increases the expression of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[15]
AM-404	DMBK9PS	Investigative	AM-404 increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[24]
BCTC	DMT5AGJ	Investigative	BCTC decreases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[11]
Saccharin	DMRA736	Investigative	Saccharin increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[25]
N-oleoyl-dopamine	DM1AVCZ	Investigative	N-oleoyl-dopamine increases the activity of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[23]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cytarabine	DMZD5QR	Approved	Cytarabine affects the localization of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[9]
Resiniferatoxin	DMP62L5	Phase 2	Resiniferatoxin affects the binding of Transient receptor potential cation channel subfamily V member 1 (TRPV1).	[8]

References

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• [3] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [7] Comparison of protective effect of ascorbic acid on redox and endocannabinoid systems interactions in in vitro cultured human skin fibroblasts exposed to UV radiation and hydrogen peroxide. Arch Dermatol Res. 2017 May;309(4):285-303. doi: 10.1007/s00403-017-1729-0. Epub 2017 Mar 11.
• [8] Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001 Oct;134(4):845-52. doi: 10.1038/sj.bjp.0704327.
• [9] Cytosine arabinoside affects the heat and capsaicin receptor TRPV1 localisation and sensitivity in human sensory neurons. J Neurooncol. 2008 Aug;89(1):1-7. doi: 10.1007/s11060-008-9585-6. Epub 2008 Apr 15.
• [10] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [11] 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.
• [12] Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol. 2004 Mar;13(3):129-39. doi: 10.1111/j.0906-6705.2004.0178.x.
• [13] The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons. J Clin Invest. 2008 Feb;118(2):763-76. doi: 10.1172/JCI32751.
• [14] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [15] 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.
• [16] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Transient receptor potential vanilloid 1 receptors mediate acid-induced mucin secretion via Ca2+ influx in human airway epithelial cells. J Biochem Mol Toxicol. 2012 May;26(5):179-86. doi: 10.1002/jbt.20413. Epub 2012 May 7.
• [19] Bisphenol A-Induced Cell Proliferation and Mitochondrial Oxidative Stress Are Diminished via Modulation of TRPV1 Channel in Estrogen Positive Breast Cancer Cell by Selenium Treatment. Biol Trace Elem Res. 2020 Nov;198(1):118-130. doi: 10.1007/s12011-020-02057-3. Epub 2020 Feb 10.
• [20] 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.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [22] Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Am J Physiol Renal Physiol. 2007 Dec;293(6):F1865-76. doi: 10.1152/ajprenal.00347.2007. Epub 2007 Oct 3.
• [23] N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J Biol Chem. 2003 Apr 18;278(16):13633-9. doi: 10.1074/jbc.M211231200. Epub 2003 Feb 4.
• [24] "TRPV1 is a component of the atrial natriuretic signaling complex, and using orally delivered antagonists, presents a valid therapeutic target in the longitudinal reversal and treatment of cardiac hypertrophy and heart failure". Channels (Austin). 2019 Dec;13(1):1-16. doi: 10.1080/19336950.2018.1547611.
• [25] Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors. Am J Physiol Regul Integr Comp Physiol. 2007 Aug;293(2):R626-34. doi: 10.1152/ajpregu.00286.2007. Epub 2007 Jun 13.
• [26] Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury. Am J Physiol Lung Cell Mol Physiol. 2012 Jan 1;302(1):L111-9. doi: 10.1152/ajplung.00231.2011. Epub 2011 Sep 23.
• [27] Induction of total insensitivity to capsaicin and hypersensitivity to garlic extract in human by decreased expression of TRPV1. Neurosci Lett. 2007 Jan 10;411(2):87-91. doi: 10.1016/j.neulet.2006.10.046. Epub 2006 Nov 15.