Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYJTL3S)

• DOT Name: Putative cytochrome P450 2D7 (CYP2D7)
• Synonyms: EC 1.14.14.1
• Gene Name: CYP2D7
• Related Disease:
  Attention deficit hyperactivity disorder
  Type-1/2 diabetes
  Advanced cancer
  Alzheimer disease
  Amelogenesis imperfecta type 1B
  Analgesia
  Autoimmune hepatitis
  Breast cancer
  Breast carcinoma
  Depression
  Gilbert syndrome
  Head and neck cancer
  Head and neck carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Non-alcoholic fatty liver disease
  Obesity
  Schizophrenia
  Treatment-refractory schizophrenia
  Hepatitis C virus infection
  Lewy body dementia
  Neoplasm
• UniProt ID: CP2D7_HUMAN
• EC Number: 1.14.14.1
• Pfam ID: PF00067
• Sequence:
  MGLEALVPLAMIVAIFLLLVDLMHRHQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQ
  LRRRFGDVFSLQLAWTPVVVLNGLAAVREAMVTRGEDTADRPPAPIYQVLGFGPRSQGVI
  LSRYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFADQAGRPFRPNGLLDK
  AVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLPHIPALAGKV
  LRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAKKEKAKGSPESSFNDENLRIVVG
  NLFLAGMVTTSTTLAWGLLLMILHLDVQRGRRVSPGCPIVGTHVCPVRVQQEIDDVIGQV
  RRPEMGDQAHMPCTTAVIHEVQHFGDIVPLGVTHMTSRDIEVQGFRIPKGTTLITNLSSV
  LKDEAVWKKPFRFHPEHFLDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQ
  HFSFSVAAGQPRPSHSRVVSFLVTPSPYELCAVPR
• Function: May be responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It may be involved in the metabolism of codeine to morphine. However, another study could not confirm it.
• Tissue Specificity: Expressed in brain cortex (at protein level).
• KEGG Pathway:
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Endocrine resistance (hsa01522)
  Serotonergic sy.pse (hsa04726)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Amelogenesis imperfecta type 1B	DISWPUI8	Strong	Biomarker	[5]
Analgesia	DISK3TVI	Strong	Altered Expression	[6]
Autoimmune hepatitis	DISOX03Q	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Depression	DIS3XJ69	Strong	Biomarker	[9]
Gilbert syndrome	DISMUZF4	Strong	Biomarker	[10]
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[11]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[11]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[12]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[12]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[13]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[14]
Obesity	DIS47Y1K	Strong	Genetic Variation	[15]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[16]
Treatment-refractory schizophrenia	DISTVVL9	Strong	Genetic Variation	[17]
Hepatitis C virus infection	DISQ0M8R	Limited	Genetic Variation	[5]
Lewy body dementia	DISAE66J	Limited	Genetic Variation	[18]
Neoplasm	DISZKGEW	Limited	Biomarker	[19]

1 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 Putative cytochrome P450 2D7 (CYP2D7).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Putative cytochrome P450 2D7 (CYP2D7).	[21]

References

• [1] Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites.Clin Pharmacol Ther. 2003 Mar;73(3):178-91. doi: 10.1067/mcp.2003.25.
• [2] Changes in tramadol enantioselective pharmacokinetics and metabolism in rats with experimental diabetes treated or not with insulin.Eur J Pharm Sci. 2019 Feb 1;128:97-102. doi: 10.1016/j.ejps.2018.11.032. Epub 2018 Nov 28.
• [3] Genetic polymorphisms of CYP2D6, GSTM1, and GSTT1 genes and bladder cancer risk in North India.Cancer Genet Cytogenet. 2005 Jan 1;156(1):68-73. doi: 10.1016/j.cancergencyto.2004.04.001.
• [4] Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease.Pharmacogenet Genomics. 2011 Apr;21(4):225-30. doi: 10.1097/FPC.0b013e32833f984c.
• [5] Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus infected patients is associated with the possession of HLA B51.Int J Immunopathol Pharmacol. 2004 Jan-Apr;17(1):83-92. doi: 10.1177/039463200401700112.
• [6] Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia.Addict Biol. 2019 Mar;24(2):228-238. doi: 10.1111/adb.12590. Epub 2017 Dec 21.
• [7] Overlapping but distinct specificities of anti-liver-kidney microsome antibodies in autoimmune hepatitis type II and hepatitis C revealed by recombinant native CYP2D6 and novel peptide epitopes.Clin Exp Immunol. 1999 Nov;118(2):290-7. doi: 10.1046/j.1365-2249.1999.01027.x.
• [8] CYP2D6 gene variants and their association with breast cancer susceptibility.Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1255-8. doi: 10.1158/1055-9965.EPI-11-0321. Epub 2011 Apr 28.
• [9] The activity of brain and liver cytochrome P450 2D (CYP2D) is differently affected by antidepressants in the chronic mild stress (CMS) model of depression in the rat.Biochem Pharmacol. 2018 Oct;156:398-405. doi: 10.1016/j.bcp.2018.09.005. Epub 2018 Sep 7.
• [10] Disposition of propafenone in a poor metabolizer of CYP2D6 with Gilbert's syndrome.Ther Drug Monit. 2000 Jun;22(3):366-8. doi: 10.1097/00007691-200006000-00020.
• [11] Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients.Mol Biol Rep. 2014;41(4):2591-600. doi: 10.1007/s11033-014-3117-6. Epub 2014 Jan 22.
• [12] Cytochrome P450 CYP2D6 gene polymorphism and lung cancer susceptibility in Caucasians.Pharmacogenetics. 1998 Feb;8(1):7-14. doi: 10.1097/00008571-199802000-00002.
• [13] Comparisons of CYP2D messenger RNA splice variant profiles in human lung tumors and normal tissues.Cancer Res. 1997 Jul 1;57(13):2589-92.
• [14] Effects of Orotic Acid-Induced Non-Alcoholic Fatty Liver on the Pharmacokinetics of Metoprolol and its Metabolites in Rats.J Pharm Pharm Sci. 2019;22(1):98-111. doi: 10.18433/jpps30268.
• [15] Statistical Binning for Barcoded Reads Improves Downstream Analyses.Cell Syst. 2018 Aug 22;7(2):219-226.e5. doi: 10.1016/j.cels.2018.07.005.
• [16] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [17] A patient with treatment-resistant schizophrenia and cytochrome P4502D6 gene duplication.Clin Genet. 2002 Feb;61(2):152-4. doi: 10.1034/j.1399-0004.2002.610211.x.
• [18] Alternative splicing patterns of CYP2D genes in human brain and neurodegenerative disorders.Neurology. 1999 Oct 22;53(7):1570-2. doi: 10.1212/wnl.53.7.1570.
• [19] Refinement of an ovarian cancer tumour suppressor gene locus on chromosome arm 22q and mutation analysis of CYP2D6, SREBP2 and NAGA.Int J Cancer. 2000 Sep 15;87(6):798-802. doi: 10.1002/1097-0215(20000915)87:6<798::aid-ijc6>3.0.co;2-x.
• [20] 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.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.