Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTLM7XN)

• DOT Name: NADH-cytochrome b5 reductase 2 (CYB5R2)
• Synonyms: b5R.2; EC 1.6.2.2
• Gene Name: CYB5R2
• Related Disease:
  Glioblastoma multiforme
  Nasopharyngeal carcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
• UniProt ID: NB5R2_HUMAN
• EC Number: 1.6.2.2
• Pfam ID: PF00970 ; PF00175
• Sequence:
  MNSRRREPITLQDPEAKYPLPLIEKEKISHNTRRFRFGLPSPDHVLGLPVGNYVQLLAKI
  DNELVVRAYTPVSSDDDRGFVDLIIKIYFKNVHPQYPEGGKMTQYLENMKIGETIFFRGP
  RGRLFYHGPGNLGIRPDQTSEPKKTLADHLGMIAGGTGITPMLQLIRHITKDPSDRTRMS
  LIFANQTEEDILVRKELEEIARTHPDQFNLWYTLDRPPIGWKYSSGFVTADMIKEHLPPP
  AKSTLILVCGPPPLIQTAAHPNLEKLGYTQDMIFTY
• Function: NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction. Responsible for NADH-dependent lucigenin chemiluminescence in spermatozoa by reducing both lucigenin and 2-[4-iodophenyl]-3-[4-nitrophenyl]-5-[2,4-disulfophenyl]-2H tetrazolium monosodium salt (WST-1).
• Tissue Specificity: Restricted expression.
• KEGG Pathway: Amino sugar and nucleotide sugar metabolism (hsa00520)
• Reactome Pathway: Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[1]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[2]
Neoplasm	DISZKGEW	moderate	Posttranslational Modification	[2]
Prostate cancer	DISF190Y	Limited	Posttranslational Modification	[3]
Prostate carcinoma	DISMJPLE	Limited	Posttranslational Modification	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[14]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of NADH-cytochrome b5 reductase 2 (CYB5R2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of NADH-cytochrome b5 reductase 2 (CYB5R2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADH-cytochrome b5 reductase 2 (CYB5R2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH-cytochrome b5 reductase 2 (CYB5R2).	[12]

References

• [1] Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma.Acta Neuropathol. 2015 Oct;130(4):587-97. doi: 10.1007/s00401-015-1470-8. Epub 2015 Sep 1.
• [2] Cytochrome b5 reductase 2 is a novel candidate tumor suppressor gene frequently inactivated by promoter hypermethylation in human nasopharyngeal carcinoma.Tumour Biol. 2014 Apr;35(4):3755-63. doi: 10.1007/s13277-013-1497-1. Epub 2013 Dec 12.
• [3] Identification of novel DNA-methylated genes that correlate with human prostate cancer and high-grade prostatic intraepithelial neoplasia.Prostate Cancer Prostatic Dis. 2013 Dec;16(4):292-300. doi: 10.1038/pcan.2013.21. Epub 2013 Jul 30.
• [4] 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.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [7] 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.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] 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.
• [14] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [15] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [16] 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.
• [17] 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.
• [18] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [19] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.