Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDFATG0)

• DOT Name: Antithrombin-III (SERPINC1)
• Synonyms: ATIII; Serpin C1
• Gene Name: SERPINC1
• Related Disease: Hereditary antithrombin deficiency
• UniProt ID: ANT3_HUMAN
• PDB ID: 1ANT; 1ATH; 1AZX; 1BR8; 1DZG; 1DZH; 1E03; 1E04; 1E05; 1JVQ; 1LK6; 1NQ9; 1OYH; 1R1L; 1SR5; 1T1F; 1TB6; 2ANT; 2B4X; 2B5T; 2BEH; 2GD4; 2HIJ; 2ZNH; 3EVJ; 3KCG; 4EB1
• Pfam ID: PF00079
• Sequence:
  MYSNVIGTVTSGKRKVYLLSLLLIGFWDCVTCHGSPVDICTAKPRDIPMNPMCIYRSPEK
  KATEDEGSEQKIPEATNRRVWELSKANSRFATTFYQHLADSKNDNDNIFLSPLSISTAFA
  MTKLGACNDTLQQLMEVFKFDTISEKTSDQIHFFFAKLNCRLYRKANKSSKLVSANRLFG
  DKSLTFNETYQDISELVYGAKLQPLDFKENAEQSRAAINKWVSNKTEGRITDVIPSEAIN
  ELTVLVLVNTIYFKGLWKSKFSPENTRKELFYKADGESCSASMMYQEGKFRYRRVAEGTQ
  VLELPFKGDDITMVLILPKPEKSLAKVEKELTPEVLQEWLDELEEMMLVVHMPRFRIEDG
  FSLKEQLQDMGLVDLFSPEKSKLPGIVAEGRDDLYVSDAFHKAFLEVNEEGSEAAASTAV
  VIAGRSLNPNRVTFKANRPFLVFIREVPLNTIIFMGRVANPCVK
• Function: Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin.
• Tissue Specificity: Found in plasma.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary antithrombin deficiency	DIS37I0W	Definitive	Semidominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Eltrombopag	DMOGFIX	Approved	Antithrombin-III (SERPINC1) increases the Thromboembolism ADR of Eltrombopag.	[23]

23 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 Antithrombin-III (SERPINC1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Antithrombin-III (SERPINC1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Antithrombin-III (SERPINC1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Antithrombin-III (SERPINC1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the activity of Antithrombin-III (SERPINC1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Antithrombin-III (SERPINC1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Antithrombin-III (SERPINC1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Antithrombin-III (SERPINC1).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Antithrombin-III (SERPINC1).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate increases the expression of Antithrombin-III (SERPINC1).	[11]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the activity of Antithrombin-III (SERPINC1).	[12]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Antithrombin-III (SERPINC1).	[13]
Ardeparin	DMYRX8B	Approved	Ardeparin decreases the expression of Antithrombin-III (SERPINC1).	[14]
Warfarin	DMJYCVW	Approved	Warfarin increases the expression of Antithrombin-III (SERPINC1).	[15]
Clofibrate	DMPC1J7	Approved	Clofibrate decreases the expression of Antithrombin-III (SERPINC1).	[15]
Busulfan	DMXYJ9C	Approved	Busulfan affects the expression of Antithrombin-III (SERPINC1).	[16]
Prednisone	DM2HG4X	Approved	Prednisone increases the expression of Antithrombin-III (SERPINC1).	[17]
Aminocaproic acid	DMFGND4	Approved	Aminocaproic acid increases the expression of Antithrombin-III (SERPINC1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Antithrombin-III (SERPINC1).	[18]
Phenformin	DMQ52JG	Withdrawn from market	Phenformin increases the activity of Antithrombin-III (SERPINC1).	[19]
Chlorotrianisene	DMSV2WZ	Withdrawn from market	Chlorotrianisene decreases the expression of Antithrombin-III (SERPINC1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Antithrombin-III (SERPINC1).	[21]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Antithrombin-III (SERPINC1).	[22]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Oral contraceptives, antithrombin- III activity, and postoperative deep-vein thrombosis. Lancet. 1976 Mar 6;1(7958):509-11. doi: 10.1016/s0140-6736(76)90296-8.
• [7] 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.
• [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] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [10] Thrombotic predisposition associated with oral contraceptives. Obstet Gynecol. 1973 Mar;41(3):427-35.
• [11] Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost. 1995 Aug;74(2):693-7.
• [12] Effects of oral and transvaginal ethinyl estradiol on hemostatic factors and hepatic proteins in a randomized, crossover study. J Clin Endocrinol Metab. 2007 Jun;92(6):2074-9. doi: 10.1210/jc.2007-0026. Epub 2007 Mar 20.
• [13] Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery. Crit Care Med. 2003 Apr;31(4):1068-74. doi: 10.1097/01.CCM.0000059646.89546.98.
• [14] Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation. 1995 Apr 1;91(7):1929-35. doi: 10.1161/01.cir.91.7.1929.
• [15] Venous thrombosis, heparin-induced antithrombin III deficiency, and factor VIII. Lancet. 1977 Dec 10;2(8050):1231-2.
• [16] Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005 May;84(5):321-30. doi: 10.1007/s00277-004-0982-4. Epub 2004 Dec 4.
• [17] Plasma proteinase inhibitor activity and hemostasis tests in children with nephrotic syndrome. Effect of prednisone alone and prednisone plus epsilon-aminocaproic acid treatment regimens: a preliminary report. Am J Ther. 2001 Mar-Apr;8(2):97-107. doi: 10.1097/00045391-200103000-00004.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [19] Sulfenamide and sulfonamide derivatives of metformin can exert anticoagulant and profibrinolytic properties. Chem Biol Interact. 2018 Mar 25;284:126-136. doi: 10.1016/j.cbi.2018.02.012. Epub 2018 Feb 16.
• [20] The effect of chlorotrianisene as postpartum lactation suppression on blood coagulation factors. Am J Obstet Gynecol. 1979 Jul 1;134(5):518-22. doi: 10.1016/0002-9378(79)90832-9.
• [21] 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.
• [22] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [23] Early onset of abdominal venous thrombosis in a newborn with homozygous type II heparin-binding site antithrombin deficiency. Blood Coagul Fibrinolysis. 2017 Apr;28(3):264-266. doi: 10.1097/MBC.0000000000000570.