Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHCWT42)

• DOT Name: Cytochrome P450 2C8 (CYP2C8)
• Synonyms: EC 1.14.14.1; CYPIIC8; Cytochrome P450 IIC2; Cytochrome P450 MP-12; Cytochrome P450 MP-20; Cytochrome P450 form 1; S-mephenytoin 4-hydroxylase
• Gene Name: CYP2C8
• UniProt ID: CP2C8_HUMAN
• PDB ID: 1PQ2; 2NNH; 2NNI; 2NNJ; 2VN0
• EC Number: 1.14.14.1
• Pfam ID: PF00067
• Sequence:
  MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKV
  YGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRW
  KEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICS
  VVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALT
  RSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTE
  TTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSD
  LVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFK
  KSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLP
  PSYQICFIPV
• Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins. 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 (NADPH--hemoprotein reductase). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond. Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form. Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol).
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Linoleic acid metabolism (hsa00591)
  Retinol metabolism (hsa00830)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
  Serotonergic sy.pse (hsa04726)
  Chemical carcinogenesis - D. adducts (hsa05204)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  CYP2E1 reactions (R-HSA-211999)
  Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) (R-HSA-2142670)
  Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) (R-HSA-2142816)
  Biosynthesis of maresin-like SPMs (R-HSA-9027307)
  Aspirin ADME (R-HSA-9749641)
  Xenobiotics (R-HSA-211981)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 13 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Cytochrome P450 2C8 (CYP2C8) increases the hydroxylation of Tretinoin.	[34]
Imatinib	DM7RJXL	Approved	Cytochrome P450 2C8 (CYP2C8) decreases the methylation of Imatinib.	[38]
Lansoprazole	DMXYLQ3	Approved	Cytochrome P450 2C8 (CYP2C8) increases the hydroxylation of Lansoprazole.	[40]
Bromfenac	DMKB79O	Approved	Cytochrome P450 2C8 (CYP2C8) increases the hydroxylation of Bromfenac.	[41]
Tolbutamide	DM02AWV	Approved	Cytochrome P450 2C8 (CYP2C8) increases the hydroxylation of Tolbutamide.	[42]
Domperidone	DMBDPY0	Approved	Cytochrome P450 2C8 (CYP2C8) increases the hydroxylation of Domperidone.	[43]
Sulfadiazine	DMTW3R8	Approved	Cytochrome P450 2C8 (CYP2C8) increases the hydroxylation of Sulfadiazine.	[42]
Almogran	DM7I64Z	Approved	Cytochrome P450 2C8 (CYP2C8) decreases the methylation of Almogran.	[44]
Aminophenazone	DMY2AH1	Phase 4	Cytochrome P450 2C8 (CYP2C8) decreases the methylation of Aminophenazone.	[20]
N-DESMETHYLCLOZAPINE	DMVIRN3	Phase 2	Cytochrome P450 2C8 (CYP2C8) increases the chemical synthesis of N-DESMETHYLCLOZAPINE.	[49]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	Cytochrome P450 2C8 (CYP2C8) increases the chemical synthesis of all-trans-4-oxo-retinoic acid.	[34]
Bufuralol	DMJSC07	Investigative	Cytochrome P450 2C8 (CYP2C8) increases the hydroxylation of Bufuralol.	[56]
Diclofenac glucuronide	DMWADLM	Investigative	Cytochrome P450 2C8 (CYP2C8) affects the hydroxylation of Diclofenac glucuronide.	[57]

This DOT Affected the Regulation of Drug Effects of 10 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Rosiglitazone	DMILWZR	Approved	Cytochrome P450 2C8 (CYP2C8) decreases the metabolism of Rosiglitazone.	[35]
Felbamate	DM1V5ZS	Approved	Cytochrome P450 2C8 (CYP2C8) increases the metabolism of Felbamate.	[45]
Chloroquine	DMSI5CB	Phase 3 Trial	Cytochrome P450 2C8 (CYP2C8) increases the metabolism of Chloroquine.	[47]
Masitinib	DMRSNEU	Phase 3	Cytochrome P450 2C8 (CYP2C8) increases the metabolism of Masitinib.	[48]
Carfentanil	DM7ADGX	Phase 2	Cytochrome P450 2C8 (CYP2C8) increases the metabolism of Carfentanil.	[50]
Vanoxerine	DMBQPA5	Discontinued in Phase 1	Cytochrome P450 2C8 (CYP2C8) decreases the degradation of Vanoxerine.	[51]
Phencyclidine	DMQBEYX	Investigative	Cytochrome P450 2C8 (CYP2C8) affects the metabolism of Phencyclidine.	[52]
Arachidonic acid	DMUOQZD	Investigative	Cytochrome P450 2C8 (CYP2C8) increases the metabolism of Arachidonic acid.	[53]
1,4-Naphthoquinone	DMTCMH7	Investigative	Cytochrome P450 2C8 (CYP2C8) increases the abundance of 1,4-Naphthoquinone.	[54]
aconitine	DMFOZ60	Investigative	Cytochrome P450 2C8 (CYP2C8) increases the metabolism of aconitine.	[55]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Cytochrome P450 2C8 (CYP2C8) increases the response to substance of Paclitaxel.	[36]
Cyclophosphamide	DM4O2Z7	Approved	Cytochrome P450 2C8 (CYP2C8) increases the activity of Cyclophosphamide.	[37]
Ifosfamide	DMCT3I8	Approved	Cytochrome P450 2C8 (CYP2C8) increases the activity of Ifosfamide.	[37]
Warfarin	DMJYCVW	Approved	Cytochrome P450 2C8 (CYP2C8) affects the response to substance of Warfarin.	[39]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Cytochrome P450 2C8 (CYP2C8) decreases the response to substance of Chlorpromazine.	[46]

60 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 Cytochrome P450 2C8 (CYP2C8).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Cytochrome P450 2C8 (CYP2C8).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Cytochrome P450 2C8 (CYP2C8).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cytochrome P450 2C8 (CYP2C8).	[7]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cytochrome P450 2C8 (CYP2C8).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Cytochrome P450 2C8 (CYP2C8).	[9]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[11]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Cytochrome P450 2C8 (CYP2C8).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Cytochrome P450 2C8 (CYP2C8).	[13]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Cytochrome P450 2C8 (CYP2C8).	[14]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[15]
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[16]
Ritonavir	DMU764S	Approved	Ritonavir decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[17]
Lovastatin	DM9OZWQ	Approved	Lovastatin decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[18]
Isoniazid	DM5JVS3	Approved	Isoniazid decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[16]
Clotrimazole	DMMFCIH	Approved	Clotrimazole decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Nifedipine	DMSVOZT	Approved	Nifedipine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Loratadine	DMF3AN7	Approved	Loratadine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Zafirlukast	DMHNQOG	Approved	Zafirlukast decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Spironolactone	DM2AQ5N	Approved	Spironolactone decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil increases the expression of Cytochrome P450 2C8 (CYP2C8).	[19]
Felodipine	DMOSW35	Approved	Felodipine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Nortriptyline	DM4KDYJ	Approved	Nortriptyline decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[16]
Amoxicillin	DMUYNEI	Approved	Amoxicillin decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[20]
Dabrafenib	DMX6OE3	Approved	Dabrafenib decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[21]
Pazopanib	DMF57DM	Approved	Pazopanib increases the expression of Cytochrome P450 2C8 (CYP2C8).	[22]
Salmeterol	DMIEU69	Approved	Salmeterol decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Sulfinpyrazone	DMEV954	Approved	Sulfinpyrazone decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[23]
Phenelzine	DMHIDUE	Approved	Phenelzine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[16]
Medroxyprogesterone	DMBGWPH	Approved	Medroxyprogesterone decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[24]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[22]
MLN8237	DMO8PT9	Phase 3	MLN8237 affects the activity of Cytochrome P450 2C8 (CYP2C8).	[25]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[16]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[16]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[26]
(Z)-endoxifen	DMGDOS2	Phase 2	(Z)-endoxifen decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[27]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID decreases the expression of Cytochrome P450 2C8 (CYP2C8).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[28]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Cytochrome P450 2C8 (CYP2C8).	[29]
LICOAGROCHACONE A	DMWY0TN	Investigative	LICOAGROCHACONE A decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[30]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[24]
CITCO	DM0N634	Investigative	CITCO increases the expression of Cytochrome P450 2C8 (CYP2C8).	[8]
L-thyroxine	DM83HWL	Investigative	L-thyroxine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Fibrates	DMFNTMY	Investigative	Fibrates increases the expression of Cytochrome P450 2C8 (CYP2C8).	[19]
Irbesartan	DMTP1DC	Investigative	Irbesartan decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]
Cinnamic acid	DM340FH	Investigative	Cinnamic acid decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[31]
DIOSMETIN	DM4KXIM	Investigative	DIOSMETIN decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[32]
2-(5-fluoro-1H-indol-3-yl)ethanamine	DMHW5FT	Investigative	2-(5-fluoro-1H-indol-3-yl)ethanamine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[33]
Oxybutynine	DMJPBAX	Investigative	Oxybutynine decreases the activity of Cytochrome P450 2C8 (CYP2C8).	[10]

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