Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTAQ6ZW)

• DTT Name: Cytochrome P450 2A6 (CYP2A6)
• Synonyms: Cytochrome P450(I); Cytochrome P450 IIA3; Coumarin 7-hydroxylase; CYPIIA6; CYP2A6; CYP2A3
• Gene Name: CYP2A6
• DTT Type: Successful target; [1]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: CP2A6_HUMAN
• TTD ID: T06455
• EC Number: EC 1.14.13.-
• Sequence:
  MLASGMLLVALLVCLTVMVLMSVWQQRKSKGKLPPGPTPLPFIGNYLQLNTEQMYNSLMK
  ISERYGPVFTIHLGPRRVVVLCGHDAVREALVDQAEEFSGRGEQATFDWVFKGYGVVFSN
  GERAKQLRRFSIATLRDFGVGKRGIEERIQEEAGFLIDALRGTGGANIDPTFFLSRTVSN
  VISSIVFGDRFDYKDKEFLSLLRMMLGIFQFTSTSTGQLYEMFSSVMKHLPGPQQQAFQL
  LQGLEDFIAKKVEHNQRTLDPNSPRDFIDSFLIRMQEEEKNPNTEFYLKNLVMTTLNLFI
  GGTETVSTTLRYGFLLLMKHPEVEAKVHEEIDRVIGKNRQPKFEDRAKMPYMEAVIHEIQ
  RFGDVIPMSLARRVKKDTKFRDFFLPKGTEVYPMLGSVLRDPSFFSNPQDFNPQHFLNEK
  GQFKKSDAFVPFSIGKRNCFGEGLARMELFLFFTTVMQNFRLKSSQSPKDIDVSPKHVGF
  ATIPRNYTMSFLPR
• Function: Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Possesses low phenacetin O-deethylation activity.
• 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 - DNA adducts (hsa05204)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  CYP2E1 reactions (R-HSA-211999)
  Xenobiotics (R-HSA-211981)
• BioCyc Pathway: MetaCyc:HS10343-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Methoxsalen	DME8FZ9	Cutaneous T-cell lymphoma	2B01	Approved	[2]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Cytochrome P450 2A6 (CYP2A6) DME Info
• Gene Name: CYP2A6

48 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[3]
Apremilast	DMTWS9E	Psoriasis vulgaris	EA90	Approved	[4]
Arformoterol	DMYM974	Chronic obstructive pulmonary disease	CA22	Approved	[5]
Artemisinin	DMOY7W3	Malaria	1F40-1F45	Approved	[6]
Artesunate	DMR27C8	Infection of P. falciparum	1F40	Approved	[7]
Azelastine	DMXTMBJ	Allergic conjunctivitis	9A60.02	Approved	[8]
Camphor	DMWIO46	Acute or chronic pain	MG30-MG31	Approved	[9]
Cenobamate	DM8KLU9	Complex partial seizure	8A68.0	Approved	[10]
Chlorzoxazone	DMCYVDT	Acute pain	MG31	Approved	[11]
Cinnarizine	DM7U5QJ	Meniere disease	AB31.0	Approved	[12]
Cisapride	DMY7PED	Gastroesophageal reflux disease	DA22.Z	Approved	[13]
Clofibrate	DMPC1J7	Dysbetalipoproteinemia	5C80.2	Approved	[14]
Clozapine	DMFC71L	Schizophrenia	6A20	Approved	[15]
Cyclophosphamide	DM4O2Z7	Advanced cancer	2A00-2F9Z	Approved	[16]
Dapagliflozin	DM28UJG	Non-insulin dependent diabetes	5A11	Approved	[17]
Dexmedetomidine	DM93L4X	Irritability	MB24	Approved	[18]
Flunarizine	DMZU5JP	Migraine	8A80	Approved	[14]
Flunitrazepam	DMGR5Z3	Insomnia	7A00-7A0Z	Approved	[19]
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[20]
Flurazepam	DMAL4G0	Insomnia	7A00-7A0Z	Approved	[21]
Halothane	DM80OZ5	Anaesthesia	9A78.6	Approved	[22]
Ifosfamide	DMCT3I8	Adult central nervous system germ cell tumor		Approved	[23]
Letrozole	DMH07Y3	Estrogen-receptor positive breast cancer		Approved	[24]
Lidocaine	DML4ZOT	Anaesthesia	9A78.6	Approved	[25]
Lorcaserin	DMG6OYJ	Obesity	5B81	Approved	[26]
Marinol	DM70IK5	Anorexia nervosa cachexia	6B80	Approved	[27]
Methoxsalen	DME8FZ9	Cutaneous T-cell lymphoma	2B01	Approved	[6]
Methoxyflurane	DML0RAE	Anaesthesia	9A78.6	Approved	[28]
Metronidazole	DMTIVEN	Abscess		Approved	[29]
Montelukast	DMD157S	Allergic asthma	CA23.0	Approved	[12]
Nevirapine	DM6HX9B	Human immunodeficiency virus infection	1C62	Approved	[12]
Nicotine	DMWX5CO	Lung cancer	2C25.0	Approved	[30]
Norethindrone acetate	DMDGCQP	N. A.	N. A.	Approved	[31]
Perazine	DM2AOTZ	Psychotic disorder	6A20-6A25	Approved	[32]
Pilocarpine	DMV9ADG	Glaucoma/ocular hypertension	9C61	Approved	[33]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[25]
Propofol	DMB4OLE	Anaesthesia	9A78.6	Approved	[34]
Selegiline Hydrochloride	DM3VR1L	Parkinson disease	8A00.0	Approved	[35]
Sevoflurane	DMC9O43	Anaesthesia	9A78.6	Approved	[28]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[36]
Tegafur	DM31ZQM	Solid tumour/cancer	2A00-2F9Z	Approved	[37]
Thalidomide	DM70BU5	Adult T-cell leukemia/lymphoma		Approved	[38]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[25]
UFT	DMX3O0D	Solid tumour/cancer	2A00-2F9Z	Approved	[39]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[40]
Vortioxetine	DM6F1PU	Major depressive disorder	6A70.3	Approved	[41]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[25]
Medifoxamine	DM0UGYX	N. A.	N. A.	Phase 4	[25]

5 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
5-methoxypsoralen	DME2A8X	Psoriasis vulgaris	EA90	Phase 3	[42]
Clomethiazole	DMSPN58	Stroke	8B20	Phase 3	[25]
Plitidepsin	DMJ8AUE	Multiple myeloma	2A83	Phase 3	[43]
BMS 650032	DMQI43G	Hepatitis C virus infection	1E51.1	Phase 2	[44]
Roxatidine	DMIZMYQ	N. A.	N. A.	Phase 2	[45]

1 Discontinued Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Phenacetin	DMRQAM0	Analgesia	MB40.8	Withdrawn from market	[46]

7 Investigative Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Chloroxylenol	DMM75WZ	N. A.	N. A.	Investigative	[25]
Fenthion	DMKEG49	N. A.	N. A.	Investigative	[47]
Fenthion sulfoxide	DM4OLRS	N. A.	N. A.	Investigative	[47]
flavone	DMEQH6J	Discovery agent	N.A.	Investigative	[48]
Levoverbenone	DMV3P89	N. A.	N. A.	Investigative	[49]
Nicotinyl alcohol	DMO7M2N	N. A.	N. A.	Investigative	[50]
Phenazone	DMCE985	Discovery agent	N.A.	Investigative	[51]

References

• [1] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [2] Mutagenicity and carcinogenicity of methoxsalen plus UV-A. Arch Dermatol. 1984 May;120(5):662-9.
• [3] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [4] Apremilast (Otezla): a new oral treatment for adults with psoriasis and psoriatic arthritis. P T. 2015 Aug;40(8):495-500.
• [5] A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos. 2007 Oct;35(10):1797-805.
• [6] Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol. 1999 Oct;48(4):528-35.
• [7] Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42.
• [8] Azelastine N-demethylation by cytochrome P-450 (CYP)3A4, CYP2D6, and CYP1A2 in human liver microsomes: evaluation of approach to predict the contribution of multiple CYPs. Drug Metab Dispos. 1999 Dec;27(12):1381-91.
• [9] In vitro metabolism of (-)-camphor using human liver microsomes and CYP2A6. Biol Pharm Bull. 2007 Feb;30(2):230-3.
• [10] FDA label of Cenobamate. The 2020 official website of the U.S. Food and Drug Administration.
• [11] Prediction of human liver microsomal oxidations of 7-ethoxycoumarin and chlorzoxazone with kinetic parameters of recombinant cytochrome P-450 enzymes. Drug Metab Dispos. 1999 Nov;27(11):1274-80.
• [12] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [13] Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions. Br J Pharmacol. 2000 Apr;129(8):1655-67.
• [14] Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes. Biol Pharm Bull. 1996 Nov;19(11):1511-4.
• [15] Characterization of human cytochrome P450s involved in the bioactivation of clozapine. Drug Metab Dispos. 2013 Mar;41(3):651-8.
• [16] Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos. 1999 Jun;27(6):655-66.
• [17] Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014 Jan;53(1):17-27.
• [18] Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication. Expert Rev Clin Pharmacol. 2018 Sep;11(9):917-922.
• [19] CYP3A4 is the major CYP isoform mediating the in vitro hydroxylation and demethylation of flunitrazepam. Drug Metab Dispos. 2001 Feb;29(2):133-40.
• [20] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [21] Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab Dispos. 2009 Jan;37(1):10-3.
• [22] Halothane-dependent lipid peroxidation in human liver microsomes is catalyzed by cytochrome P4502A6 (CYP2A6). Anesthesiology. 2001 Aug;95(2):509-14.
• [23] Measurement of 4-hydroxylation of ifosfamide in human liver microsomes using the estimation of free and protein-bound acrolein and codetermination of keto- and carboxyifosfamide. J Cancer Res Clin Oncol. 2002 Jul;128(7):385-92.
• [24] Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res Treat. 2018 Nov;172(2):371-379.
• [25] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [26] Identification of human cytochrome P450 and flavin-containing monooxygenase enzymes involved in the metabolism of lorcaserin, a novel selective human 5-hydroxytryptamine 2C agonist. Drug Metab Dispos. 2012 Apr;40(4):761-71.
• [27] Health control over the feeding of troops on the Western and 3d Belorussian Fronts during the Great Patriotic War years. Voen Med Zh. 1975 Jun;(6):86-8.
• [28] Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology. 1995 Mar;82(3):689-99.
• [29] The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
• [30] CYP2A6- and CYP2A13-catalyzed metabolism of the nicotine delta-5'(1')iminium ion. J Pharmacol Exp Ther. 2012 Nov;343(2):307-15.
• [31] Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone. J Steroid Biochem Mol Biol. 2008 May;110(1-2):56-66.
• [32] The metabolism of the piperazine-type phenothiazine neuroleptic perazine by the human cytochrome P-450 isoenzymes. Eur Neuropsychopharmacol. 2004 May;14(3):199-208.
• [33] Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine. FEBS J. 2012 May;279(9):1621-31.
• [34] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [35] Variation in CYP2A6 activity and personalized medicine. J Pers Med. 2017 Dec 1;7(4). pii: E18.
• [36] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [37] Rapid development of S-1 in the west for therapy of advanced gastric carcinoma. Gan To Kagaku Ryoho. 2006 Jun;33 Suppl 1:117-20.
• [38] Metabolism of thalidomide in human microsomes, cloned human cytochrome P-450 isozymes, and Hansen's disease patients. J Biochem Mol Toxicol. 2000;14(3):140-7.
• [39] UFT Capsules (uracil-tegafur).
• [40] Psychotropic drug interactions with valproate. Clin Neuropharmacol. 2005 Mar-Apr;28(2):96-101.
• [41] Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant, Lu AA21004. Drug Metab Dispos. 2012 Jul;40(7):1357-65.
• [42] Cytochrome P450 CYP1B1 interacts with 8-methoxypsoralen (8-MOP) and influences psoralen-ultraviolet A (PUVA) sensitivity. PLoS One. 2013 Sep 23;8(9):e75494.
• [43] In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19.
• [44] Australian Public Assessment Report for asunaprevir.
• [45] Cytochrome P450 enzymes involved in the metabolic pathway of the histamine 2 (H2)-receptor antagonist roxatidine acetate by human liver microsomes. Arzneimittelforschung. 2001;51(8):651-8.
• [46] Activation of phenacetin O-deethylase activity by alpha-naphthoflavone in human liver microsomes. Xenobiotica. 1999 Sep;29(9):885-98.
• [47] The participation of human hepatic P450 isoforms, flavin-containing monooxygenases and aldehyde oxidase in the biotransformation of the insecticide fenthion. Toxicol Appl Pharmacol. 2008 Dec 1;233(2):343-52.
• [48] Site-specific oxidation of flavanone and flavone by cytochrome P450 2A6 in human liver microsomes. Xenobiotica. 2019 Jul;49(7):791-802.
• [49] Roles of human CYP2A6 and 2B6 and rat CYP2C11 and 2B1 in the 10-hydroxylation of (-)-verbenone by liver microsomes. Drug Metab Dispos. 2003 Aug;31(8):1049-53.
• [50] Stability of the nicotine metabolite ratio in ad libitum and reducing smokers. Cancer Epidemiol Biomarkers Prev. 2008 Jun;17(6):1396-400.
• [51] Identification of the human hepatic cytochromes P450 involved in the in vitro oxidation of antipyrine. Drug Metab Dispos. 1996 Apr;24(4):487-94.