Details of Drug Off-Target (DOT)

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

• DOT Name: Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1)
• Synonyms: ITI heavy chain H1; ITI-HC1; Inter-alpha-inhibitor heavy chain 1; Inter-alpha-trypsin inhibitor complex component III; Serum-derived hyaluronan-associated protein; SHAP
• Gene Name: ITIH1
• Related Disease:
  Type-1/2 diabetes
  Advanced cancer
  Anxiety
  Bipolar depression
  Bipolar disorder
  Breast neoplasm
  Colitis
  Inflammatory bowel disease
  Knee osteoarthritis
  Liver cancer
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Mood disorder
  Neoplasm
  Parkinson disease
  Osteoarthritis
  Rheumatoid arthritis
  Schizoaffective disorder
  Schizophrenia
  Von willebrand disease
• UniProt ID: ITIH1_HUMAN
• PDB ID: 6FPY; 6FPZ
• Pfam ID: PF06668 ; PF08487 ; PF00092
• Sequence:
  MDGAMGPRGLLLCMYLVSLLILQAMPALGSATGRSKSSEKRQAVDTAVDGVFIRSLKVNC
  KVTSRFAHYVVTSQVVNTANEAREVAFDLEIPKTAFISDFAVTADGNAFIGDIKDKVTAW
  KQYRKAAISGENAGLVRASGRTMEQFTIHLTVNPQSKVTFQLTYEEVLKRNHMQYEIVIK
  VKPKQLVHHFEIDVDIFEPQGISKLDAQASFLPKELAAQTIKKSFSGKKGHVLFRPTVSQ
  QQSCPTCSTSLLNGHFKVTYDVSRDKICDLLVANNHFAHFFAPQNLTNMNKNVVFVIDIS
  GSMRGQKVKQTKEALLKILGDMQPGDYFDLVLFGTRVQSWKGSLVQASEANLQAAQDFVR
  GFSLDEATNLNGGLLRGIEILNQVQESLPELSNHASILIMLTDGDPTEGVTDRSQILKNV
  RNAIRGRFPLYNLGFGHNVDFNFLEVMSMENNGRAQRIYEDHDATQQLQGFYSQVAKPLL
  VDVDLQYPQDAVLALTQNHHKQYYEGSEIVVAGRIADNKQSSFKADVQAHGEGQEFSITC
  LVDEEEMKKLLRERGHMLENHVERLWAYLTIQELLAKRMKVDREERANLSSQALQMSLDY
  GFVTPLTSMSIRGMADQDGLKPTIDKPSEDSPPLEMLGPRRTFVLSALQPSPTHSSSNTQ
  RLPDRVTGVDTDPHFIIHVPQKEDTLCFNINEEPGVILSLVQDPNTGFSVNGQLIGNKAR
  SPGQHDGTYFGRLGIANPATDFQLEVTPQNITLNPGFGGPVFSWRDQAVLRQDGVVVTIN
  KKRNLVVSVDDGGTFEVVLHRVWKGSSVHQDFLGFYVLDSHRMSARTHGLLGQFFHPIGF
  EVSDIHPGSDPTKPDATMVVRNRRLTVTRGLQKDYSKDPWHGAEVSCWFIHNNGAGLIDG
  AYTDYIVPDIF
• 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.; Contains a potential peptide which could stimulate a broad spectrum of phagocytotic cells.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Bipolar depression	DISA75FU	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[6]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[7]
Liver cancer	DISDE4BI	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[2]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[2]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[9]
Mood disorder	DISLVMWO	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[11]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[12]
Rheumatoid arthritis	DISTSB4J	moderate	Altered Expression	[12]
Schizoaffective disorder	DISLBW6B	moderate	Genetic Variation	[13]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[14]
Von willebrand disease	DIS3TZCH	Limited	Biomarker	[15]

11 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 H1 (ITIH1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[21]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[24]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[25]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1).	[22]

References

• [1] Overproduction of inter--trypsin inhibitor heavy chain 1 after loss of G(13) in liver exacerbates systemic insulin resistance in mice.Sci Transl Med. 2019 Oct 9;11(513):eaan4735. doi: 10.1126/scitranslmed.aan4735.
• [2] Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: a systematic expression analysis.BMC Cancer. 2008 Jan 28;8:25. doi: 10.1186/1471-2407-8-25.
• [3] 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.
• [4] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [5] The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation.Oncogene. 2008 Jan 31;27(6):865-76. doi: 10.1038/sj.onc.1210669. Epub 2007 Jul 23.
• [6] 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.
• [7] Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019 Feb;51(2):230-236.
• [8] A comparison of transcriptomic and metabonomic technologies for identifying biomarkers predictive of two-year rodent cancer bioassays.Toxicol Sci. 2007 Mar;96(1):40-6. doi: 10.1093/toxsci/kfl171. Epub 2006 Nov 17.
• [9] ITIH family genes confer risk to schizophrenia and major depressive disorder in the Han Chinese population.Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jun 3;51:34-8. doi: 10.1016/j.pnpbp.2013.12.004. Epub 2014 Jan 2.
• [10] 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.
• [11] A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci.Nat Genet. 2017 Oct;49(10):1511-1516. doi: 10.1038/ng.3955. Epub 2017 Sep 11.
• [12] Discovery of circulating proteins associated to knee radiographic osteoarthritis.Sci Rep. 2017 Mar 9;7(1):137. doi: 10.1038/s41598-017-00195-8.
• [13] GWAS meta analysis identifies TSNARE1 as a novel Schizophrenia / Bipolar susceptibility locus.Sci Rep. 2013 Oct 29;3:3075. doi: 10.1038/srep03075.
• [14] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [15] Decreased ITIH5 expression is associated with poor prognosis in primary gastric cancer.Med Oncol. 2014 Jul;31(7):53. doi: 10.1007/s12032-014-0053-1. Epub 2014 Jun 10.
• [16] 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.
• [17] 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.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 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.
• [21] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [22] 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.
• [23] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [26] 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.