Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9R0YLY)

• DOT Name: Histamine H2 receptor (HRH2)
• Synonyms: H2R; HH2R; Gastric receptor I
• Gene Name: HRH2
• UniProt ID: HRH2_HUMAN
• PDB ID: 7UL3
• Pfam ID: PF00001
• Sequence:
  MAPNGTASSFCLDSTACKITITVVLAVLILITVAGNVVVCLAVGLNRRLRNLTNCFIVSL
  AITDLLLGLLVLPFSAIYQLSCKWSFGKVFCNIYTSLDVMLCTASILNLFMISLDRYCAV
  MDPLRYPVLVTPVRVAISLVLIWVISITLSFLSIHLGWNSRNETSKGNHTTSKCKVQVNE
  VYGLVDGLVTFYLPLLIMCITYYRIFKVARDQAKRINHISSWKAATIREHKATVTLAAVM
  GAFIICWFPYFTAFVYRGLRGDDAINEVLEAIVLWLGYANSALNPILYAALNRDFRTGYQ
  QLFCCRLANRNSHKTSLRSNASQLSRTQSREPRQQEEKPLKLQVWSGTEVTAPQGATDR
• Function: The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Gastric acid secretion (hsa04971)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Histamine receptors (R-HSA-390650)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	Histamine H2 receptor (HRH2) increases the abundance of [3H]cAMP.	[8]

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 Histamine H2 receptor (HRH2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Histamine H2 receptor (HRH2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Histamine H2 receptor (HRH2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histamine H2 receptor (HRH2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histamine H2 receptor (HRH2).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Histamine H2 receptor (HRH2).	[5]
Ergotidine	DM78IME	Approved	Ergotidine increases the activity of Histamine H2 receptor (HRH2).	[6]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells. J Immunol. 2005 May 1;174(9):5224-32. doi: 10.4049/jimmunol.174.9.5224.
• [7] 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.
• [8] Constitutive activity and structural instability of the wild-type human H2 receptor. J Neurochem. 1998 Aug;71(2):799-807.