Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRJ3P2Z)

• DOT Name: Cytochrome P450 2A7 (CYP2A7)
• Synonyms: EC 1.14.14.1; CYPIIA7; Cytochrome P450 IIA4
• Gene Name: CYP2A7
• Related Disease:
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Myotonic dystrophy
  Ovarian cancer
  Ovarian neoplasm
  Advanced cancer
  Brain neoplasm
  Glioblastoma multiforme
  Neoplasm
  Chronic obstructive pulmonary disease
• UniProt ID: CP2A7_HUMAN
• EC Number: 1.14.14.1
• Pfam ID: PF00067
• Sequence:
  MLASGLLLVALLACLTVMVLMSVWQQRKSRGKLPPGPTPLPFIGNYLQLNTEHICDSIMK
  FSECYGPVFTIHLGPRRVVVLCGHDAVREALVDQAEEFSGRGEQATFDWVFKGYGVAFSN
  GERAKQLLRFAIATLRDFGVGKRGIEERIQEESGFLIEAIRSTHGANIDPTFFLSRTVSN
  VISSIVFGDRFDYEDKEFLSLLSMMLGIFQFTSTSTGQLYEMFSSVMKHLPGPQQQAFKL
  LQGLEDFIAKKVEHNQRTLDPNSPQDFIDSFLIHMQEEEKNPNTEFYLKNLMMSTLNLFI
  AGTETVSTTLRYGFLLLMKHPEVEAKVHEEIDRVIGKNRQPKFEDRTKMPYMEAVIHEIQ
  RFGDVIPMSLARRVKKDTKFRDFFLPKGTEVFPMLGSVLRDPSFFSNPQDFNPQHFLDDK
  GQFKKSDAFVPFSIGKRNCFGEGLARMELFLFFTTVMQNFRLKSSQSPKDIDVSPKHVVF
  ATIPRNYTMSFLPR
• Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
• KEGG Pathway:
  Caffeine metabolism (hsa00232)
  Retinol metabolism (hsa00830)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis - D. adducts (hsa05204)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Xenobiotics (R-HSA-211981)
  CYP2E1 reactions (R-HSA-211999)
  Fatty acids (R-HSA-211935)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[1]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[1]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Brain neoplasm	DISY3EKS	moderate	Biomarker	[6]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[7]

9 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 2A7 (CYP2A7).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 2A7 (CYP2A7).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytochrome P450 2A7 (CYP2A7).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cytochrome P450 2A7 (CYP2A7).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cytochrome P450 2A7 (CYP2A7).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Cytochrome P450 2A7 (CYP2A7).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cytochrome P450 2A7 (CYP2A7).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cytochrome P450 2A7 (CYP2A7).	[12]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Cytochrome P450 2A7 (CYP2A7).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytochrome P450 2A7 (CYP2A7).	[13]

References

• [1] Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.Eur J Hum Genet. 2017 Apr;25(4):432-438. doi: 10.1038/ejhg.2016.203. Epub 2017 Feb 1.
• [2] Chromosome 19q13 disruption alters expressions of CYP2A7, MIA and MIA-RAB4B lncRNA and contributes to FAP-like phenotype in APC mutation-negative familial colorectal cancer patients.PLoS One. 2017 Mar 17;12(3):e0173772. doi: 10.1371/journal.pone.0173772. eCollection 2017.
• [3] Molecular mimicry of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T cell recognition.J Exp Med. 1999 Jul 19;190(2):169-76. doi: 10.1084/jem.190.2.169.
• [4] Cytochrome P450 family members are associated with fast-growing hepatocellular carcinoma and patient survival: An integrated analysis of gene expression profiles.Saudi J Gastroenterol. 2019 May-Jun;25(3):167-175. doi: 10.4103/sjg.SJG_290_18.
• [5] Linkage relationships of the apolipoprotein C1 gene and a cytochrome P450 gene (CYP2A) to myotonic dystrophy.Hum Genet. 1990 Aug;85(3):305-10. doi: 10.1007/BF00206751.
• [6] Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy.J Pharmacol Exp Ther. 2014 Jun;349(3):458-69. doi: 10.1124/jpet.114.214619. Epub 2014 Apr 2.
• [7] Common and Rare Variants Genetic Association Analysis of Cigarettes per Day Among Ever-Smokers in Chronic Obstructive Pulmonary Disease Cases and Controls.Nicotine Tob Res. 2019 May 21;21(6):714-722. doi: 10.1093/ntr/nty095.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] 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.
• [14] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.