Details of Drug Off-Target (DOT)

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

• DOT Name: Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH)
• Synonyms: ETF-QO; ETF-ubiquinone oxidoreductase; EC 1.5.5.1; Electron-transferring-flavoprotein dehydrogenase; ETF dehydrogenase
• Gene Name: ETFDH
• Related Disease:
  Hepatocellular carcinoma
  Multiple acyl-CoA dehydrogenase deficiency
  Carnitine palmitoyltransferase II deficiency
  Coenzyme Q10 deficiency
  Metabolic disorder
  Obesity
  Dorfman-Chanarin disease
  Hypoglycemia
  Neutral lipid storage myopathy
  Systemic primary carnitine deficiency disease
• UniProt ID: ETFD_HUMAN
• EC Number: 1.5.5.1
• Pfam ID: PF05187 ; PF21162 ; PF01946
• Sequence:
  MLVPLAKLSCLAYQCFHALKIKKNYLPLCATRWSSTSTVPRITTHYTIYPRDKDKRWEGV
  NMERFAEEADVVIVGAGPAGLSAAVRLKQLAVAHEKDIRVCLVEKAAQIGAHTLSGACLD
  PGAFKELFPDWKEKGAPLNTPVTEDRFGILTEKYRIPVPILPGLPMNNHGNYIVRLGHLV
  SWMGEQAEALGVEVYPGYAAAEVLFHDDGSVKGIATNDVGIQKDGAPKATFERGLELHAK
  VTIFAEGCHGHLAKQLYKKFDLRANCEPQTYGIGLKELWVIDEKNWKPGRVDHTVGWPLD
  RHTYGGSFLYHLNEGEPLVALGLVVGLDYQNPYLSPFREFQRWKHHPSIRPTLEGGKRIA
  YGARALNEGGFQSIPKLTFPGGLLIGCSPGFMNVPKIKGTHTAMKSGILAAESIFNQLTS
  ENLQSKTIGLHVTEYEDNLKNSWVWKELYSVRNIRPSCHGVLGVYGGMIYTGIFYWILRG
  MEPWTLKHKGSDFERLKPAKDCTPIEYPKPDGQISFDLLSSVALSGTNHEHDQPAHLTLR
  DDSIPVNRNLSIYDGPEQRFCPAGVYEFVPVEQGDGFRLQINAQNCVHCKTCDIKDPSQN
  INWVVPEGGGGPAYNGM
• Function: Accepts electrons from ETF and reduces ubiquinone.
• Reactome Pathway: Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:HS10326-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Multiple acyl-CoA dehydrogenase deficiency	DISEFBN7	Definitive	Autosomal recessive	[2]
Carnitine palmitoyltransferase II deficiency	DIS3GFD9	Strong	Genetic Variation	[3]
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[4]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[6]
Dorfman-Chanarin disease	DISKKT3R	Limited	Biomarker	[7]
Hypoglycemia	DISRCKR7	Limited	Biomarker	[8]
Neutral lipid storage myopathy	DISR9UYD	Limited	Biomarker	[7]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[7]

16 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 Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[20]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (ETFDH).	[16]

References

• [1] Expression and significance of ETFDH in hepatocellular carcinoma.Pathol Res Pract. 2019 Dec;215(12):152702. doi: 10.1016/j.prp.2019.152702. Epub 2019 Oct 23.
• [2] 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.
• [3] Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease-different clinical entities and comparable perinatal renal abnormalities.Pediatr Nephrol. 2017 May;32(5):791-800. doi: 10.1007/s00467-016-3556-5. Epub 2017 Jan 12.
• [4] The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.Brain. 2007 Aug;130(Pt 8):2037-44. doi: 10.1093/brain/awm054. Epub 2007 Apr 5.
• [5] ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.Neuromuscul Disord. 2009 Mar;19(3):212-6. doi: 10.1016/j.nmd.2009.01.008. Epub 2009 Feb 26.
• [6] Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers.J Physiol Biochem. 2011 Mar;67(1):15-26. doi: 10.1007/s13105-010-0044-4. Epub 2010 Sep 30.
• [7] Clinical and genetic analysis of lipid storage myopathies.Muscle Nerve. 2009 Mar;39(3):333-42. doi: 10.1002/mus.21167.
• [8] Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II.Mol Genet Metab. 2008 Jan;93(1):36-9. doi: 10.1016/j.ymgme.2007.09.015. Epub 2007 Oct 31.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [21] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.