Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8F9FV6)

• DOT Name: Histamine H1 receptor (HRH1)
• Synonyms: H1R; HH1R
• Gene Name: HRH1
• UniProt ID: HRH1_HUMAN
• PDB ID: 3RZE; 7DFL
• Pfam ID: PF00001
• Sequence:
  MSLPNSSCLLEDKMCEGNKTTMASPQLMPLVVVLSTICLVTVGLNLLVLYAVRSERKLHT
  VGNLYIVSLSVADLIVGAVVMPMNILYLLMSKWSLGRPLCLFWLSMDYVASTASIFSVFI
  LCIDRYRSVQQPLRYLKYRTKTRASATILGAWFLSFLWVIPILGWNHFMQQTSVRREDKC
  ETDFYDVTWFKVMTAIINFYLPTLLMLWFYAKIYKAVRQHCQHRELINRSLPSFSEIKLR
  PENPKGDAKKPGKESPWEVLKRKPKDAGGGSVLKSPSQTPKEMKSPVVFSQEDDREVDKL
  YCFPLDIVHMQAAAEGSSRDYVAVNRSHGQLKTDEQGLNTHGASEISEDQMLGDSQSFSR
  TDSDTTTETAPGKGKLRSGSNTGLDYIKFTWKRLRSHSRQYVSGLHMNRERKAAKQLGFI
  MAAFILCWIPYFIFFMVIAFCKNCCNEHLHMFTIWLGYINSTLNPLIYPLCNENFKKTFK
  RILHIRS
• Function: In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Histamine receptors (R-HSA-390650)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ropivacaine	DMSPJG2	Approved	Histamine H1 receptor (HRH1) affects the binding of Ropivacaine.	[17]
Lidocaine	DML4ZOT	Approved	Histamine H1 receptor (HRH1) affects the binding of Lidocaine.	[17]
Lamotrigine	DM8SXYG	Approved	Histamine H1 receptor (HRH1) increases the response to substance of Lamotrigine.	[18]
Gabapentin	DM6T924	Approved	Histamine H1 receptor (HRH1) increases the Sleep disturbances (incl subtypes) ADR of Gabapentin.	[19]
Tetracaine	DM9J6C2	Approved	Histamine H1 receptor (HRH1) affects the binding of Tetracaine.	[17]
Procaine	DM4LSNE	Approved	Histamine H1 receptor (HRH1) affects the binding of Procaine.	[17]
Bupivacaine	DM4PRFC	Approved	Histamine H1 receptor (HRH1) affects the binding of Bupivacaine.	[17]

3 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 Histamine H1 receptor (HRH1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Histamine H1 receptor (HRH1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histamine H1 receptor (HRH1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Histamine H1 receptor (HRH1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histamine H1 receptor (HRH1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histamine H1 receptor (HRH1).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Histamine H1 receptor (HRH1).	[5]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Histamine H1 receptor (HRH1).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Histamine H1 receptor (HRH1).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Histamine H1 receptor (HRH1).	[9]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of Histamine H1 receptor (HRH1).	[11]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Histamine H1 receptor (HRH1).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Histamine H1 receptor (HRH1).	[15]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Histamine H1 receptor (HRH1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Clozapine affects the binding of Histamine H1 receptor (HRH1).	[8]
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the binding of Histamine H1 receptor (HRH1).	[8]
Loratadine	DMF3AN7	Approved	Loratadine affects the binding of Histamine H1 receptor (HRH1).	[10]
Desloratadine	DM56YN7	Approved	Desloratadine affects the binding of Histamine H1 receptor (HRH1).	[10]
OX-NLA	DMPEHBJ	Discontinued in Phase 3	OX-NLA affects the binding of Histamine H1 receptor (HRH1).	[10]

References

• [1] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [7] 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.
• [8] No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J. 2007 Aug;7(4):275-81. doi: 10.1038/sj.tpj.6500418. Epub 2006 Sep 19.
• [9] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [10] Cetirizine and loratadine-based antihistamines with 5-lipoxygenase inhibitory activity. Bioorg Med Chem Lett. 2004 Nov 15;14(22):5591-4.
• [11] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [12] Quercetin inhibits transcriptional up-regulation of histamine H1 receptor via suppressing protein kinase C-/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 signaling pathway in HeLa cells. Int Immunopharmacol. 2013 Feb;15(2):232-9. doi: 10.1016/j.intimp.2012.12.030. Epub 2013 Jan 16.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [16] Tributyltin role on the serotonin and histamine receptors in human umbilical artery. Toxicol In Vitro. 2018 Aug;50:210-216. doi: 10.1016/j.tiv.2018.03.006. Epub 2018 Mar 24.
• [17] H(1)R mediates local anesthetic-induced vascular permeability in angioedema. Toxicol Appl Pharmacol. 2020 Apr 1;392:114921. doi: 10.1016/j.taap.2020.114921. Epub 2020 Feb 12.
• [18] Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression. J Clin Psychiatry. 2010 May;71(5):599-605. doi: 10.4088/JCP.08m04632gre. Epub 2009 Dec 15.
• [19] 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.