Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBJO49O)

• DOT Name: Histamine H4 receptor (HRH4)
• Synonyms: H4R; HH4R; AXOR35; G-protein coupled receptor 105; GPRv53; Pfi-013; SP9144
• Gene Name: HRH4
• UniProt ID: HRH4_HUMAN
• PDB ID: 7YFC; 7YFD
• Pfam ID: PF00001
• Sequence:
  MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAIS
  DFFVGVISIPLYIPHTLFEWDFGKEICVFWLTTDYLLCTASVYNIVLISYDRYLSVSNAV
  SYRTQHTGVLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSF
  LEFVIPVILVAYFNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSA
  STEVPASFHSERQRRKSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARR
  LAKSLAILLGVFAVCWAPYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPL
  CHKRFQKAFLKIFCIKKQPLPSQHSRSVSS
• Function: The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist).
• Tissue Specificity: Expressed primarily in the bone marrow and eosinophils. Shows preferential distribution in cells of immunological relevance such as T-cells, dendritic cells, monocytes, mast cells, neutrophils. Also expressed in a wide variety of peripheral tissues, including the heart, kidney, liver, lung, pancreas, skeletal muscle, prostate, small intestine, spleen, testis, colon, fetal liver and lymph node.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Histamine receptors (R-HSA-390650)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Clobenpropit	DM537OH	Investigative	Histamine H4 receptor (HRH4) increases the response to substance of Clobenpropit.	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histamine H4 receptor (HRH4).	[1]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Histamine H4 receptor (HRH4).	[2]
Ergotidine	DM78IME	Approved	Ergotidine increases the activity of Histamine H4 receptor (HRH4).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
5'-Guanosine-Diphosphate-Monothiophosphate	DMIARG7	Investigative	5'-Guanosine-Diphosphate-Monothiophosphate affects the binding of Histamine H4 receptor (HRH4).	[4]

References

• [1] Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells. Toxicol Appl Pharmacol. 2016 Sep 1;306:8-16. doi: 10.1016/j.taap.2016.06.028. Epub 2016 Jun 28.
• [2] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [3] 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.
• [4] Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther. 2001 Mar;296(3):1058-66.
• [5] Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression. PLoS One. 2012;7(2):e31207. doi: 10.1371/journal.pone.0031207. Epub 2012 Feb 20.