Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXSB1AE)

• DOT Name: Cytochrome P450 2W1 (CYP2W1)
• Synonyms: EC 1.14.14.-; CYPIIW1
• Gene Name: CYP2W1
• Related Disease:
  Adrenal gland neoplasm
  Adrenocortical carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Stomach cancer
  Colonic neoplasm
  Squamous cell carcinoma
  Colon adenocarcinoma
  Hyperglycemia
  Neoplasm
  Obesity
• UniProt ID: CP2W1_HUMAN
• EC Number: 1.14.14.-
• Pfam ID: PF00067
• Sequence:
  MALLLLLFLGLLGLWGLLCACAQDPSPAARWPPGPRPLPLVGNLHLLRLSQQDRSLMELS
  ERYGPVFTVHLGRQKTVVLTGFEAVKEALAGPGQELADRPPIAIFQLIQRGGGIFFSSGA
  RWRAARQFTVRALHSLGVGREPVADKILQELKCLSGQLDGYRGRPFPLALLGWAPSNITF
  ALLFGRRFDYRDPVFVSLLGLIDEVMVLLGSPGLQLFNVYPWLGALLQLHRPVLRKIEEV
  RAILRTLLEARRPHVCPGDPVCSYVDALIQQGQGDDPEGLFAEANAVACTLDMVMAGTET
  TSATLQWAALLMGRHPDVQGRVQEELDRVLGPGRTPRLEDQQALPYTSAVLHEVQRFITL
  LPHVPRCTAADTQLGGFLLPKGTPVIPLLTSVLLDETQWQTPGQFNPGHFLDANGHFVKR
  EAFLPFSAGRRVCVGERLARTELFLLFAGLLQRYRLLPPPGVSPASLDTTPARAFTMRPR
  AQALCAVPRP
• Function: A cytochrome P450 monooxygenase that may play a role in retinoid and phospholipid metabolism. Catalyzes the hydroxylation of saturated carbon hydrogen bonds. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may regulate atRA clearance. Other retinoids such as all-trans retinol and all-trans retinal are potential endogenous substrates. Catalyzes both epoxidation of double bonds and hydroxylation of carbon hydrogen bonds of the fatty acyl chain of 1-acylphospholipids/2-lysophospholipids. Can metabolize various lysophospholipids classes including lysophosphatidylcholines (LPCs), lysophosphatidylinositols (LPIs), lysophosphatidylserines (LPSs), lysophosphatidylglycerols (LPGs), lysophosphatidylethanolamines (LPEs) and lysophosphatidic acids (LPAs). Has low or no activity toward 2-acylphospholipids/1-lysophospholipids, diacylphospholipids and free fatty acids. May play a role in tumorigenesis by activating procarcinogens such as aflatoxin B1, polycyclic aromatic hydrocarbon dihydrodiols and aromatic amines. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).
• Tissue Specificity: Very low levels are detected in fetal and adult tissues. Highly expressed in several tumor samples, in particular colon and adrenal tumors.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Xenobiotics (R-HSA-211981)
  Miscellaneous substrates (R-HSA-211958)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenal gland neoplasm	DISFK7RF	Strong	Altered Expression	[1]
Adrenocortical carcinoma	DISZF4HX	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Colonic neoplasm	DISSZ04P	moderate	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[7]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[8]
Hyperglycemia	DIS0BZB5	Limited	Genetic Variation	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Obesity	DIS47Y1K	Limited	Genetic Variation	[9]

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 Cytochrome P450 2W1 (CYP2W1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytochrome P450 2W1 (CYP2W1).	[18]

8 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 Cytochrome P450 2W1 (CYP2W1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome P450 2W1 (CYP2W1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 2W1 (CYP2W1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome P450 2W1 (CYP2W1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cytochrome P450 2W1 (CYP2W1).	[15]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cytochrome P450 2W1 (CYP2W1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytochrome P450 2W1 (CYP2W1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytochrome P450 2W1 (CYP2W1).	[19]

References

• [1] Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1.Biochem Biophys Res Commun. 2006 Mar 10;341(2):451-8. doi: 10.1016/j.bbrc.2005.12.200. Epub 2006 Jan 11.
• [2] Human Cytochrome P450 2W1 Is Not Expressed in Adrenal Cortex and Is Only Rarely Expressed in Adrenocortical Carcinomas.PLoS One. 2016 Sep 6;11(9):e0162379. doi: 10.1371/journal.pone.0162379. eCollection 2016.
• [3] Cytochrome P450 2W1 (CYP2W1) - ready for use as the biomarker and drug target for cancer?.Xenobiotica. 2017 Oct;47(10):923-932. doi: 10.1080/00498254.2016.1244370. Epub 2016 Oct 24.
• [4] Expression of CYP2S1 and CYP2W1 in breast cancer epithelial cells and modulation of their expression by synthetic methoxy stilbenes.Pharmacol Rep. 2019 Dec;71(6):1001-1005. doi: 10.1016/j.pharep.2019.08.005. Epub 2019 Aug 14.
• [5] Membrane topology and search for potential redox partners of colon cancer-specific cytochrome P450 2W1.FEBS Lett. 2016 Feb;590(3):330-9. doi: 10.1002/1873-3468.12063. Epub 2016 Feb 2.
• [6] Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer.Oncogene. 2006 Apr 20;25(17):2546-57. doi: 10.1038/sj.onc.1209279.
• [7] KRT13, FAIM2 and CYP2W1 mRNA expression in oral squamous cell carcinoma patients with risk habits.Asian Pac J Cancer Prev. 2015;16(3):953-8. doi: 10.7314/apjcp.2015.16.3.953.
• [8] Developmental regulation and induction of cytochrome P450 2W1, an enzyme expressed in colon tumors.PLoS One. 2015 Apr 6;10(4):e0122820. doi: 10.1371/journal.pone.0122820. eCollection 2015.
• [9] CYP2W1, CYP4F11 and CYP8A1 polymorphisms and interaction of CYP2W1 genotypes with risk factors in Mexican women with breast cancer.Asian Pac J Cancer Prev. 2012;13(3):837-46. doi: 10.7314/apjcp.2012.13.3.837.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classic aryl hydrocarbon receptor ligands. J Pharmacol Exp Ther. 2006 Dec;319(3):1162-71.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.