Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6SN4RM)

• DOT Name: Cytochrome b5 (CYB5A)
• Synonyms: Microsomal cytochrome b5 type A; MCB5
• Gene Name: CYB5A
• Related Disease:
  Methemoglobinemia type 4
  Obsolete 46,XY disorder of sex development due to isolated 17,20-lyase deficiency
• UniProt ID: CYB5_HUMAN
• PDB ID: 2I96
• Pfam ID: PF00173
• Sequence:
  MAEQSDEAVKYYTLEEIQKHNHSKSTWLILHHKVYDLTKFLEEHPGGEEVLREQAGGDAT
  ENFEDVGHSTDAREMSKTFIIGELHPDDRPKLNKPPETLITTIDSSSSWWTNWVIPAISA
  VAVALMYRLYMAED
• Function: Cytochrome b5 is a membrane-bound hemoprotein functioning as an electron carrier for several membrane-bound oxygenases.
• Reactome Pathway:
  (Name not found)
  Vitamin C (ascorbate) metabolism (R-HSA-196836)
• BioCyc Pathway: MetaCyc:ENSG00000166347-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
Methemoglobinemia type 4	DISHTKKG	Strong	Autosomal recessive	[1]
Obsolete 46,XY disorder of sex development due to isolated 17,20-lyase deficiency	DIS5BTLG	Supportive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Indomethacin	DMSC4A7	Approved	Cytochrome b5 (CYB5A) increases the Metabolic disorder ADR of Indomethacin.	[27]
Topotecan	DMP6G8T	Approved	Cytochrome b5 (CYB5A) affects the response to substance of Topotecan.	[28]

25 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 Cytochrome b5 (CYB5A).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome b5 (CYB5A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome b5 (CYB5A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytochrome b5 (CYB5A).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome b5 (CYB5A).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome b5 (CYB5A).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome b5 (CYB5A).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytochrome b5 (CYB5A).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytochrome b5 (CYB5A).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cytochrome b5 (CYB5A).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Cytochrome b5 (CYB5A).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cytochrome b5 (CYB5A).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cytochrome b5 (CYB5A).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome b5 (CYB5A).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Cytochrome b5 (CYB5A).	[16]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Cytochrome b5 (CYB5A).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytochrome b5 (CYB5A).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Cytochrome b5 (CYB5A).	[19]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Cytochrome b5 (CYB5A).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome b5 (CYB5A).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cytochrome b5 (CYB5A).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytochrome b5 (CYB5A).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytochrome b5 (CYB5A).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytochrome b5 (CYB5A).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Cytochrome b5 (CYB5A).	[26]

References

• [1] Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X. J Clin Endocrinol Metab. 2010 Mar;95(3):994-9. doi: 10.1210/jc.2008-1745. Epub 2010 Jan 15.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [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] 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] 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.
• [10] 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.
• [11] 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.
• [12] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [13] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] 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.
• [16] Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity (Silver Spring). 2010 Jan;18(1):27-34. doi: 10.1038/oby.2009.208. Epub 2009 Jun 25.
• [17] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [20] Regulation of cytochrome b5 gene transcription by Sp3, GATA-6, and steroidogenic factor 1 in human adrenal NCI-H295A cells. Mol Endocrinol. 2005 Aug;19(8):2020-34.
• [21] 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.
• [22] 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.
• [23] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [24] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] 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.
• [28] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.