Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS351DV)

• DOT Name: HIG1 domain family member 1A, mitochondrial (HIGD1A)
• Synonyms: Hypoxia-inducible gene 1 protein; RCF1 homolog A; RCF1a
• Gene Name: HIGD1A
• UniProt ID: HIG1A_HUMAN
• PDB ID: 2LOM
• Pfam ID: PF04588
• Sequence:
  MSTDTGVSLPSYEEDQGSKLIRKAKEAPFVPVGIAGFAAIVAYGLYKLKSRGNTKMSIHL
  IHMRVAAQGFVVGAMTVGMGYSMYREFWAKPKP
• Function: Proposed subunit of cytochrome c oxidase (COX, complex IV), which is the terminal component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water. May play a role in the assembly of respiratory supercomplexes.
• Reactome Pathway: Regulation of gene expression by Hypoxia-inducible Factor (R-HSA-1234158)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[10]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of HIG1 domain family member 1A, mitochondrial (HIGD1A).	[16]

References

• [1] 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.
• [2] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [12] 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.
• [13] 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.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.