Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7G5JTT)

• DOT Name: EH domain-containing protein 4 (EHD4)
• Synonyms: Hepatocellular carcinoma-associated protein 10/11; PAST homolog 4
• Gene Name: EHD4
• Related Disease:
  Deafness
  Arrhythmia
• UniProt ID: EHD4_HUMAN
• Pfam ID: PF18150 ; PF00350 ; PF12763 ; PF16880
• Sequence:
  MFSWMGRQAGGRERAGGADAVQTVTGGLRSLYLRKVLPLEEAYRFHEFHSPALEDADFEN
  KPMILLVGQYSTGKTTFIRYLLEQDFPGMRIGPEPTTDSFIAVMYGETEGSTPGNALVVD
  PKKPFRKLSRFGNAFLNRFMCSQLPNQVLKSISVIDSPGILSGEKQRISRGYDFCQVLQW
  FAERVDRIILLFDAHKLDISDEFSEAIKAFRGQDDKIRVVLNKADQVDTQQLMRVYGALM
  WSLGKVINTPEVLRVYIGSFWAQPLQNTDNRRLFEAEAQDLFRDIQSLPQKAAVRKLNDL
  IKRARLAKVHAYIISYLKKEMPSVFGKENKKRELISRLPEIYIQLQREYQISAGDFPEVK
  AMQEQLENYDFTKFHSLKPKLIEAVDNMLSNKISPLMNLISQEETSTPTQLVQGGAFDGT
  TEGPFNQGYGEGAKEGADEEEWVVAKDKPVYDELFYTLSPINGKISGVNAKKEMVTSKLP
  NSVLGKIWKLADCDCDGMLDEEEFALAKHLIKIKLDGYELPSSLPPHLVPPSHRKSLPKA
  D
• Function: ATP- and membrane-binding protein that probably controls membrane reorganization/tubulation upon ATP hydrolysis. Plays a role in early endosomal transport.
• Tissue Specificity: Highly expressed in pancreas and heart.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Deafness	DISKCLH4	Strong	Biomarker	[1]
Arrhythmia	DISFF2NI	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of EH domain-containing protein 4 (EHD4).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of EH domain-containing protein 4 (EHD4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of EH domain-containing protein 4 (EHD4).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of EH domain-containing protein 4 (EHD4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of EH domain-containing protein 4 (EHD4).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of EH domain-containing protein 4 (EHD4).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of EH domain-containing protein 4 (EHD4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of EH domain-containing protein 4 (EHD4).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of EH domain-containing protein 4 (EHD4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of EH domain-containing protein 4 (EHD4).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of EH domain-containing protein 4 (EHD4).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of EH domain-containing protein 4 (EHD4).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of EH domain-containing protein 4 (EHD4).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of EH domain-containing protein 4 (EHD4).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of EH domain-containing protein 4 (EHD4).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of EH domain-containing protein 4 (EHD4).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of EH domain-containing protein 4 (EHD4).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of EH domain-containing protein 4 (EHD4).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of EH domain-containing protein 4 (EHD4).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of EH domain-containing protein 4 (EHD4).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of EH domain-containing protein 4 (EHD4).	[20]

References

• [1] EHD4 and CDH23 are interacting partners in cochlear hair cells.J Biol Chem. 2009 Jul 24;284(30):20121-9. doi: 10.1074/jbc.M109.025668. Epub 2009 Jun 1.
• [2] Microtubular remodeling and decreased expression of Nav1.5 with enhanced EHD4 in cells from the infarcted heart.Life Sci. 2018 May 15;201:72-80. doi: 10.1016/j.lfs.2018.03.024. Epub 2018 Mar 10.
• [3] 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.
• [4] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [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] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.