Details of Drug Off-Target (DOT)

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

• DOT Name: Vitamin K epoxide reductase complex subunit 1
• Synonyms: EC 1.17.4.4; Vitamin K1 2,3-epoxide reductase subunit 1
• Gene Name: VKORC1
• Related Disease:
  Vitamin K-dependent clotting factors, combined deficiency of, type 2
  Vitamin K-dependent clotting factors, combined deficiency of, type 1
• UniProt ID: VKOR1_HUMAN
• PDB ID: 6WV3; 6WV4; 6WV5; 6WV6; 6WV7; 6WVH
• EC Number: 1.17.4.4
• Pfam ID: PF07884
• Sequence:
  MGSTWGSPGWVRLALCLTGLVLSLYALHVKAARARDRDYRALCDVGTAISCSRVFSSRWG
  RGFGLVEHVLGQDSILNQSNSIFGCIFYTLQLLLGCLRTRWASVLMLLSSLVSLAGSVYL
  AWILFFVLYDFCIVCITTYAINVSLMWLSFRKVQEPQGKAKRH
• Function: Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.
• Tissue Specificity: Expressed at highest levels in fetal and adult liver, followed by fetal heart, kidney, and lung, adult heart, and pancreas.
• KEGG Pathway:
  Ubiquinone and other terpenoid-quinone biosynthesis (hsa00130)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Metabolism of vitamin K (R-HSA-6806664)
• BioCyc Pathway: MetaCyc:HS15548-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Vitamin K-dependent clotting factors, combined deficiency of, type 2	DISXHJRT	Moderate	Autosomal recessive	[1]
Vitamin K-dependent clotting factors, combined deficiency of, type 1	DIS1X7PX	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Vitamin K epoxide reductase complex subunit 1 increases the response to substance of Aspirin.	[12]
Rifampicin	DM5DSFZ	Approved	Vitamin K epoxide reductase complex subunit 1 affects the response to substance of Rifampicin.	[13]
Warfarin	DMJYCVW	Approved	Vitamin K epoxide reductase complex subunit 1 decreases the response to substance of Warfarin.	[14]
Acenocoumarol	DMH75KV	Approved	Vitamin K epoxide reductase complex subunit 1 decreases the response to substance of Acenocoumarol.	[15]
Coumarin	DM0N8ZM	Investigative	Vitamin K epoxide reductase complex subunit 1 decreases the response to substance of Coumarin.	[16]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phytonadione	DM8HDOL	Approved	Vitamin K epoxide reductase complex subunit 1 increases the reduction of Phytonadione.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Vitamin K epoxide reductase complex subunit 1.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Vitamin K epoxide reductase complex subunit 1.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vitamin K epoxide reductase complex subunit 1.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Vitamin K epoxide reductase complex subunit 1.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vitamin K epoxide reductase complex subunit 1.	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Vitamin K epoxide reductase complex subunit 1.	[8]
Dicumarol	DMFQCB1	Approved	Dicumarol decreases the activity of Vitamin K epoxide reductase complex subunit 1.	[9]
Phenprocoumon	DMDO279	Approved	Phenprocoumon decreases the activity of Vitamin K epoxide reductase complex subunit 1.	[9]
Phenindione	DM2PYNR	Approved	Phenindione decreases the activity of Vitamin K epoxide reductase complex subunit 1.	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Vitamin K epoxide reductase complex subunit 1.	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Vitamin K epoxide reductase complex subunit 1.	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Vitamin K epoxide reductase complex subunit 1.	[10]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Vitamin K epoxide reductase complex subunit 1.	[11]
Benzotetronic acid	DM4OKXI	Investigative	Benzotetronic acid decreases the activity of Vitamin K epoxide reductase complex subunit 1.	[9]

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] Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004 Feb 5;427(6974):537-41. doi: 10.1038/nature02214.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] VKORC1 and VKORC1L1 have distinctly different oral anticoagulant dose-response characteristics and binding sites. Blood Adv. 2018 Mar 27;2(6):691-702.
• [10] 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.
• [11] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [12] VKORC1-1639 G>A Polymorphism and the Risk of Non-Variceal Upper Gastrointestinal Bleeding. J Gastrointestin Liver Dis. 2017 Mar;26(1):13-18. doi: 10.15403/jgld.2014.1121.261.vko.
• [13] Warfarin-Rifampin-Gene (WARIF-G) Interaction: A?Retrospective, Genetic, Case-Control Study. Clin Pharmacol Ther. 2023 May;113(5):1150-1159. doi: 10.1002/cpt.2871. Epub 2023 Mar 9.
• [14] The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost. 2006 May;95(5):782-7.
• [15] A vitamin K epoxide reductase-oxidase complex gene polymorphism (-1639G>A) and interindividual variability in the dose-effect of vitamin K antagonists. J Appl Genet. 2009;50(4):399-403. doi: 10.1007/BF03195700.
• [16] [New insight in therapeutic anticoagulation by Coumarin derivatives]. Hamostaseologie. 2008 Feb;28(1-2):44-50.