Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9F303M)

• DOT Name: Histamine N-methyltransferase (HNMT)
• Synonyms: HMT; EC 2.1.1.8
• Gene Name: HNMT
• Related Disease:
  Intellectual disability, autosomal recessive 51
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: HNMT_HUMAN
• PDB ID: 1JQD; 1JQE; 2AOT; 2AOU; 2AOV; 2AOW; 2AOX
• EC Number: 2.1.1.8
• Pfam ID: PF13489
• Sequence:
  MASSMRSLFSDHGKYVESFRRFLNHSTEHQCMQEFMDKKLPGIIGRIGDTKSEIKILSIG
  GGAGEIDLQILSKVQAQYPGVCINNEVVEPSAEQIAKYKELVAKTSNLENVKFAWHKETS
  SEYQSRMLEKKELQKWDFIHMIQMLYYVKDIPATLKFFHSLLGTNAKMLIIVVSGSSGWD
  KLWKKYGSRFPQDDLCQYITSDDLTQMLDNLGLKYECYDLLSTMDISDCFIDGNENGDLL
  WDFLTETCNFNATAPPDLRAELGKDLQEPEFSAKKEGKVLFNNTLSFIVIEA
• Function: Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine.
• KEGG Pathway:
  Histidine metabolism (hsa00340)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Histidine catabolism (R-HSA-70921)
  Metabolism of ingested SeMet, Sec, MeSec into H2Se (R-HSA-2408508)
• BioCyc Pathway: MetaCyc:HS07674-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal recessive 51	DIS41350	Strong	Autosomal recessive	[1]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Histamine N-methyltransferase (HNMT) affects the response to substance of Aspirin.	[21]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ergotidine	DM78IME	Approved	Histamine N-methyltransferase (HNMT) increases the methylation of Ergotidine.	[22]

21 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 Histamine N-methyltransferase (HNMT).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Histamine N-methyltransferase (HNMT).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histamine N-methyltransferase (HNMT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histamine N-methyltransferase (HNMT).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histamine N-methyltransferase (HNMT).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histamine N-methyltransferase (HNMT).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Histamine N-methyltransferase (HNMT).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Histamine N-methyltransferase (HNMT).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Histamine N-methyltransferase (HNMT).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Histamine N-methyltransferase (HNMT).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Histamine N-methyltransferase (HNMT).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Histamine N-methyltransferase (HNMT).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histamine N-methyltransferase (HNMT).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Histamine N-methyltransferase (HNMT).	[9]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Histamine N-methyltransferase (HNMT).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Histamine N-methyltransferase (HNMT).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Histamine N-methyltransferase (HNMT).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histamine N-methyltransferase (HNMT).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histamine N-methyltransferase (HNMT).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histamine N-methyltransferase (HNMT).	[19]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Histamine N-methyltransferase (HNMT).	[20]

References

• [1] Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. Hum Mol Genet. 2015 Oct 15;24(20):5697-710. doi: 10.1093/hmg/ddv286. Epub 2015 Jul 23.
• [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] 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.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] 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.
• [20] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [21] Genetic and ethnic risk factors associated with drug hypersensitivity. Curr Opin Allergy Clin Immunol. 2010 Aug;10(4):280-90. doi: 10.1097/ACI.0b013e32833b1eb3.
• [22] Structure and function of human histamine N-methyltransferase: critical enzyme in histamine metabolism in airway. Am J Physiol. 1994 Sep;267(3 Pt 1):L342-9.