Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4SLMLY)

• DOT Name: Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3)
• Synonyms: ITI heavy chain H3; ITI-HC3; Inter-alpha-inhibitor heavy chain 3; Serum-derived hyaluronan-associated protein; SHAP
• Gene Name: ITIH3
• Related Disease:
  Attention deficit hyperactivity disorder
  Anxiety
  Autism
  Bipolar disorder
  Colitis
  Inflammatory bowel disease
  Major depressive disorder
  Mental disorder
  Mood disorder
  Myocardial infarction
  Hepatocellular carcinoma
  Schizophrenia
• UniProt ID: ITIH3_HUMAN
• Pfam ID: PF06668 ; PF08487 ; PF00092
• Sequence:
  MAFAWWPCLILALLSSLAASGFPRSPFRLLGKRSLPEGVANGIEVYSTKINSKVTSRFAH
  NVVTMRAVNRADTAKEVSFDVELPKTAFITNFTLTIDGVTYPGNVKEKEVAKKQYEKAVS
  QGKTAGLVKASGRKLEKFTVSVNVAAGSKVTFELTYEELLKRHKGKYEMYLKVQPKQLVK
  HFEIEVDIFEPQGISMLDAEASFITNDLLGSALTKSFSGKKGHVSFKPSLDQQRSCPTCT
  DSLLNGDFTITYDVNRESPGNVQIVNGYFVHFFAPQGLPVVPKNVAFVIDISGSMAGRKL
  EQTKEALLRILEDMQEEDYLNFILFSGDVSTWKEHLVQATPENLQEARTFVKSMEDKGMT
  NINDGLLRGISMLNKAREEHRIPERSTSIVIMLTDGDANVGESRPEKIQENVRNAIGGKF
  PLYNLGFGNNLNYNFLENMALENHGFARRIYEDSDADLQLQGFYEEVANPLLTGVEMEYP
  ENAILDLTQNTYQHFYDGSEIVVAGRLVDEDMNSFKADVKGHGATNDLTFTEEVDMKEME
  KALQERDYIFGNYIERLWAYLTIEQLLEKRKNAHGEEKENLTARALDLSLKYHFVTPLTS
  MVVTKPEDNEDERAIADKPGEDAEATPVSPAMSYLTSYQPPQNPYYYVDGDPHFIIQIPE
  KDDALCFNIDEAPGTVLRLIQDAVTGLTVNGQITGDKRGSPDSKTRKTYFGKLGIANAQM
  DFQVEVTTEKITLWNRAVPSTFSWLDTVTVTQDGLSMMINRKNMVVSFGDGVTFVVVLHQ
  VWKKHPVHRDFLGFYVVDSHRMSAQTHGLLGQFFQPFDFKVSDIRPGSDPTKPDATLVVK
  NHQLIVTRGSQKDYRKDASIGTKVVCWFVHNNGEGLIDGVHTDYIVPNLF
• Function: May act as a carrier of hyaluronan in serum or as a binding protein between hyaluronan and other matrix protein, including those on cell surfaces in tissues to regulate the localization, synthesis and degradation of hyaluronan which are essential to cells undergoing biological processes.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Genetic Variation	[1]
Anxiety	DISIJDBA	Strong	Genetic Variation	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[4]
Colitis	DISAF7DD	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[6]
Mood disorder	DISLVMWO	Strong	Biomarker	[7]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[8]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[9]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[10]

5 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 Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3).	[15]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3).	[17]

References

• [1] Family-based association study of the arsenite methyltransferase gene (AS3MT, rs11191454) in Korean children with attention-deficit hyperactivity disorder.Psychiatr Genet. 2015 Feb;25(1):26-30. doi: 10.1097/YPG.0000000000000064.
• [2] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [3] Replication of previous GWAS hits suggests the association between rs4307059 near MSNP1AS and autism in a Chinese Han population.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8;92:194-198. doi: 10.1016/j.pnpbp.2018.12.016. Epub 2019 Jan 3.
• [4] Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression.Mol Psychiatry. 2020 Jul;25(7):1420-1429. doi: 10.1038/s41380-018-0336-6. Epub 2019 Jan 9.
• [5] Serum-Derived Hyaluronan-Associated Protein Is a Novel Biomarker for Inflammatory Bowel Diseases.Digestion. 2017;95(2):146-155. doi: 10.1159/000456071. Epub 2017 Feb 4.
• [6] ITIH3 and ITIH4 polymorphisms and depressive symptoms during pregnancy in Japan: the Kyushu Okinawa Maternal and Child Health Study.J Neural Transm (Vienna). 2018 Oct;125(10):1503-1509. doi: 10.1007/s00702-018-1905-1. Epub 2018 Jul 10.
• [7] Inter--inhibitor deficiency in the mouse is associated with alterations in anxiety-like behavior, exploration and social approach.Genes Brain Behav. 2019 Jan;18(1):e12505. doi: 10.1111/gbb.12505. Epub 2018 Aug 6.
• [8] A functional SNP in ITIH3 is associated with susceptibility to myocardial infarction.J Hum Genet. 2007;52(3):220-229. doi: 10.1007/s10038-006-0102-5. Epub 2007 Jan 9.
• [9] Discrimination of tumorigenic triazole conazoles from phenobarbital by transcriptional analyses of mouse liver gene expression.Toxicol Sci. 2009 Jul;110(1):68-83. doi: 10.1093/toxsci/kfp076. Epub 2009 Apr 10.
• [10] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [16] 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.
• [17] 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.