Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG3WBBE)

• DOT Name: Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2)
• Synonyms: ITI heavy chain H2; ITI-HC2; Inter-alpha-inhibitor heavy chain 2; Inter-alpha-trypsin inhibitor complex component II; Serum-derived hyaluronan-associated protein; SHAP
• Gene Name: ITIH2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Colitis
  Inflammatory bowel disease
  Ovarian neoplasm
  X-linked reticulate pigmentary disorder
  Stargardt disease
• UniProt ID: ITIH2_HUMAN
• Pfam ID: PF06668 ; PF08487 ; PF00092
• Sequence:
  MKRLTCFFICFFLSEVSGFEIPINGLSEFVDYEDLVELAPGKFQLVAENRRYQRSLPGES
  EEMMEEVDQVTLYSYKVQSTITSRMATTMIQSKVVNNSPQPQNVVFDVQIPKGAFISNFS
  MTVDGKTFRSSIKEKTVGRALYAQARAKGKTAGLVRSSALDMENFRTEVNVLPGAKVQFE
  LHYQEVKWRKLGSYEHRIYLQPGRLAKHLEVDVWVIEPQGLRFLHVPDTFEGHFDGVPVI
  SKGQQKAHVSFKPTVAQQRICPNCRETAVDGELVVLYDVKREEKAGELEVFNGYFVHFFA
  PDNLDPIPKNILFVIDVSGSMWGVKMKQTVEAMKTILDDLRAEDHFSVIDFNQNIRTWRN
  DLISATKTQVADAKRYIEKIQPSGGTNINEALLRAIFILNEANNLGLLDPNSVSLIILVS
  DGDPTVGELKLSKIQKNVKENIQDNISLFSLGMGFDVDYDFLKRLSNENHGIAQRIYGNQ
  DTSSQLKKFYNQVSTPLLRNVQFNYPHTSVTDVTQNNFHNYFGGSEIVVAGKFDPAKLDQ
  IESVITATSANTQLVLETLAQMDDLQDFLSKDKHADPDFTRKLWAYLTINQLLAERSLAP
  TAAAKRRITRSILQMSLDHHIVTPLTSLVIENEAGDERMLADAPPQDPSCCSGALYYGSK
  VVPDSTPSWANPSPTPVISMLAQGSQVLESTPPPHVMRVENDPHFIIYLPKSQKNICFNI
  DSEPGKILNLVSDPESGIVVNGQLVGAKKPNNGKLSTYFGKLGFYFQSEDIKIEISTETI
  TLSHGSSTFSLSWSDTAQVTNQRVQISVKKEKVVTITLDKEMSFSVLLHRVWKKHPVNVD
  FLGIYIPPTNKFSPKAHGLIGQFMQEPKIHIFNERPGKDPEKPEASMEVKGQKLIITRGL
  QKDYRTDLVFGTDVTCWFVHNSGKGFIDGHYKDYFVPQLYSFLKRP
• 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.
• Tissue Specificity: Plasma.
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Colitis	DISAF7DD	Strong	Biomarker	[2]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Biomarker	[4]
Stargardt disease	DISPXOTO	moderate	Biomarker	[5]

8 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 H2 (ITIH2).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Inter-alpha-trypsin inhibitor heavy chain H2 (ITIH2).	[15]

References

• [1] 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.
• [2] 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.
• [3] Role of serum-derived hyaluronan-associated protein-hyaluronan complex in ovarian cancer.Oncol Rep. 2008 May;19(5):1245-51.
• [4] Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy.Diabetologia. 2007 Jun;50(6):1294-303. doi: 10.1007/s00125-007-0627-y. Epub 2007 Mar 23.
• [5] Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.
• [6] 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.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
• [12] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.