Details of Drug Off-Target (DOT)

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

• DOT Name: NADH-cytochrome b5 reductase 1 (CYB5R1)
• Synonyms: b5R.1; EC 1.6.2.2; Humb5R2; NAD(P)H:quinone oxidoreductase type 3 polypeptide A2
• Gene Name: CYB5R1
• Related Disease:
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Neoplasm
• UniProt ID: NB5R1_HUMAN
• EC Number: 1.6.2.2
• Pfam ID: PF00970 ; PF00175
• Sequence:
  MGIQTSPVLLASLGVGLVTLLGLAVGSYLVRRSRRPQVTLLDPNEKYLLRLLDKTTVSHN
  TKRFRFALPTAHHTLGLPVGKHIYLSTRIDGSLVIRPYTPVTSDEDQGYVDLVIKVYLKG
  VHPKFPEGGKMSQYLDSLKVGDVVEFRGPSGLLTYTGKGHFNIQPNKKSPPEPRVAKKLG
  MIAGGTGITPMLQLIRAILKVPEDPTQCFLLFANQTEKDIILREDLEELQARYPNRFKLW
  FTLDHPPKDWAYSKGFVTADMIREHLPAPGDDVLVLLCGPPPMVQLACHPNLDKLGYSQK
  MRFTY
• Function: NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Amino sugar and nucleotide sugar metabolism (hsa00520)
• Reactome Pathway:
  Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Zalcitabine	DMH7MUV	Approved	NADH-cytochrome b5 reductase 1 (CYB5R1) increases the Cardiac disorders ADR of Zalcitabine.	[16]

1 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 NADH-cytochrome b5 reductase 1 (CYB5R1).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[8]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[9]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[10]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NADH-cytochrome b5 reductase 1 (CYB5R1).	[15]

References

• [1] CYB5R1 links epithelial-mesenchymal transition and poor prognosis in colorectal cancer.Oncotarget. 2016 May 24;7(21):31350-60. doi: 10.18632/oncotarget.8912.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [10] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.