Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUGT3G8)

• DOT Name: NADH-cytochrome b5 reductase 3 (CYB5R3)
• Synonyms: B5R; Cytochrome b5 reductase; EC 1.6.2.2; Diaphorase-1
• Gene Name: CYB5R3
• Related Disease:
  Methemoglobinemia
  Methemoglobinemia due to deficiency of methemoglobin reductase
  Hereditary methemoglobinemia
• UniProt ID: NB5R3_HUMAN
• PDB ID: 1UMK; 7THG; 7TNV; 7TSW; 7W3O
• EC Number: 1.6.2.2
• Pfam ID: PF00970 ; PF00175
• Sequence:
  MGAQLSTLGHMVLFPVWFLYSLLMKLFQRSTPAITLESPDIKYPLRLIDREIISHDTRRF
  RFALPSPQHILGLPVGQHIYLSARIDGNLVVRPYTPISSDDDKGFVDLVIKVYFKDTHPK
  FPAGGKMSQYLESMQIGDTIEFRGPSGLLVYQGKGKFAIRPDKKSNPIIRTVKSVGMIAG
  GTGITPMLQVIRAIMKDPDDHTVCHLLFANQTEKDILLRPELEELRNKHSARFKLWYTLD
  RAPEAWDYGQGFVNEEMIRDHLPPPEEEPLVLMCGPPPMIQYACLPNLDHVGHPTERCFV
  F
• Function: Catalyzes the reduction of two molecules of cytochrome b5 using NADH as the electron donor.
• Tissue Specificity: .Expressed at late stages of erythroid maturation.
• KEGG Pathway: Amino sugar and nucleotide sugar metabolism (hsa00520)
• Reactome Pathway:
  Phase I - Functionalization of compounds (R-HSA-211945)
  Neutrophil degranulation (R-HSA-6798695)
  Vitamin C (ascorbate) metabolism (R-HSA-196836)
• BioCyc Pathway: MetaCyc:HS02015-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methemoglobinemia	DISEWENH	Definitive	Autosomal recessive	[1]
Methemoglobinemia due to deficiency of methemoglobin reductase	DISZAEZH	Strong	Autosomal recessive	[2]
Hereditary methemoglobinemia	DIS4XNEP	Supportive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Indomethacin	DMSC4A7	Approved	NADH-cytochrome b5 reductase 3 (CYB5R3) increases the Metabolic disorder ADR of Indomethacin.	[19]
Zidovudine	DM4KI7O	Approved	NADH-cytochrome b5 reductase 3 (CYB5R3) increases the Mitochondrial toxicity ADR of Zidovudine.	[19]
Nicotinamide-Adenine-Dinucleotide	DM9LRKB	Investigative	NADH-cytochrome b5 reductase 3 (CYB5R3) affects the binding of Nicotinamide-Adenine-Dinucleotide.	[20]

2 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 3 (CYB5R3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADH-cytochrome b5 reductase 3 (CYB5R3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of NADH-cytochrome b5 reductase 3 (CYB5R3).	[18]

References

• [1] Serine-proline replacement at residue 127 of NADH-cytochrome b5 reductase causes hereditary methemoglobinemia, generalized type. Blood. 1990 Apr 1;75(7):1408-13.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] NADH-cytochrome b5 reductase in a Turkish family with recessive congenital methaemoglobinaemia type I. J Clin Pathol. 2008 Oct;61(10):1122-3. doi: 10.1136/jcp.2008.058701.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [16] 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.
• [17] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [18] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [19] 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.
• [20] Expression of a novel P275L variant of NADH:cytochrome b5 reductase gives functional insight into the conserved motif important for pyridine nucleotide binding. Arch Biochem Biophys. 2006 Mar 1;447(1):59-67.