Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS99MJO)

• DOT Name: Asialoglycoprotein receptor 1 (ASGR1)
• Synonyms: ASGP-R 1; ASGPR 1; C-type lectin domain family 4 member H1; Hepatic lectin H1; HL-1
• Gene Name: ASGR1
• UniProt ID: ASGR1_HUMAN
• PDB ID: 1DV8; 5JPV; 5JQ1; 6YAU
• Pfam ID: PF00059 ; PF03954
• Sequence:
  MTKEYQDLQHLDNEESDHHQLRKGPPPPQPLLQRLCSGPRLLLLSLGLSLLLLVVVCVIG
  SQNSQLQEELRGLRETFSNFTASTEAQVKGLSTQGGNVGRKMKSLESQLEKQQKDLSEDH
  SSLLLHVKQFVSDLRSLSCQMAALQGNGSERTCCPVNWVEHERSCYWFSRSGKAWADADN
  YCRLEDAHLVVVTSWEEQKFVQHHIGPVNTWMGLHDQNGPWKWVDGTDYETGFKNWRPEQ
  PDDWYGHGLGGGEDCAHFTDDGRWNDDVCQRPYRWVCETELDKASQEPPLL
• Function: Mediates the endocytosis of plasma glycoproteins to which the terminal sialic acid residue on their complex carbohydrate moieties has been removed. The receptor recognizes terminal galactose and N-acetylgalactosamine units. After ligand binding to the receptor, the resulting complex is internalized and transported to a sorting organelle, where receptor and ligand are disassociated. The receptor then returns to the cell membrane surface.
• Tissue Specificity: Expressed exclusively in hepatic parenchymal cells.
• KEGG Pathway:
  Virion - Ebolavirus and Lyssavirus (hsa03265)
  Thyroid hormone synthesis (hsa04918)
• Reactome Pathway: Asparagine N-linked glycosylation (R-HSA-446203)

Molecular Interaction Atlas (MIA) of This DOT

2 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 Asialoglycoprotein receptor 1 (ASGR1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Asialoglycoprotein receptor 1 (ASGR1).	[10]

12 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 Asialoglycoprotein receptor 1 (ASGR1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Asialoglycoprotein receptor 1 (ASGR1).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[8]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[8]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Asialoglycoprotein receptor 1 (ASGR1).	[12]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] 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.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] 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.
• [11] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [12] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.