Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUG0LEA)

• DOT Name: Alpha-2-HS-glycoprotein (AHSG)
• Synonyms: Alpha-2-Z-globulin; Ba-alpha-2-glycoprotein; Fetuin-A
• Gene Name: AHSG
• Related Disease: Alopecia-intellectual disability syndrome 1
• UniProt ID: FETUA_HUMAN
• Pfam ID: PF00031
• Sequence:
  MKSLVLLLCLAQLWGCHSAPHGPGLIYRQPNCDDPETEEAALVAIDYINQNLPWGYKHTL
  NQIDEVKVWPQQPSGELFEIEIDTLETTCHVLDPTPVARCSVRQLKEHAVEGDCDFQLLK
  LDGKFSVVYAKCDSSPDSAEDVRKVCQDCPLLAPLNDTRVVHAAKAALAAFNAQNNGSNF
  QLEEISRAQLVPLPPSTYVEFTVSGTDCVAKEATEAAKCNLLAEKQYGFCKATLSEKLGG
  AEVAVTCMVFQTQPVSSQPQPEGANEAVPTPVVDPDAPPSPPLGAPGLPPAGSPPDSHVL
  LAAPPGHQLHRAHYDLRHTFMGVVSLGSPSGEVSHPRKTRTVVQPSVGAAAGPVVPPCPG
  RIRHFKV
• Function: Promotes endocytosis, possesses opsonic properties and influences the mineral phase of bone. Shows affinity for calcium and barium ions.
• Tissue Specificity: Synthesized in liver and selectively concentrated in bone matrix. Secreted in plasma. It is also found in dentin in much higher quantities than other plasma proteins.
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Neutrophil degranulation (R-HSA-6798695)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alopecia-intellectual disability syndrome 1	DISPV4U0	Limited	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	Alpha-2-HS-glycoprotein (AHSG) increases the response to substance of Dexamethasone.	[18]
Terbutaline	DMD4381	Approved	Alpha-2-HS-glycoprotein (AHSG) increases the response to substance of Terbutaline.	[19]

14 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 Alpha-2-HS-glycoprotein (AHSG).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Alpha-2-HS-glycoprotein (AHSG).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Alpha-2-HS-glycoprotein (AHSG).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Alpha-2-HS-glycoprotein (AHSG).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Alpha-2-HS-glycoprotein (AHSG).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Alpha-2-HS-glycoprotein (AHSG).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Alpha-2-HS-glycoprotein (AHSG).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-2-HS-glycoprotein (AHSG).	[16]

References

• [1] Association of AHSG with alopecia and mental retardation (APMR) syndrome. Hum Genet. 2017 Mar;136(3):287-296. doi: 10.1007/s00439-016-1756-5. Epub 2017 Jan 4.
• [2] 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.
• [3] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [13] 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.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [15] Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. J Proteome Res. 2014 Dec 5;13(12):5734-42. doi: 10.1021/pr500714a. Epub 2014 Oct 29.
• [16] 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.
• [17] 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.
• [18] Mechanisms of dexamethasone-induced disturbed sleep and fatigue in paediatric patients receiving treatment for ALL. Eur J Cancer. 2010 Jul;46(10):1848-55. doi: 10.1016/j.ejca.2010.03.026. Epub 2010 Apr 17.
• [19] Polymorphism of the AHSG gene is associated with increased adipocyte beta2-adrenoceptor function. J Lipid Res. 2005 Oct;46(10):2278-81. doi: 10.1194/jlr.M500201-JLR200. Epub 2005 Jul 16.