Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome P450 4F2 (CYP4F2)
• Synonyms: EC 1.14.14.1; 20-hydroxyeicosatetraenoic acid synthase; 20-HETE synthase; Arachidonic acid omega-hydroxylase; CYPIVF2; Cytochrome P450-LTB-omega; Docosahexaenoic acid omega-hydroxylase; EC 1.14.14.79; Leukotriene-B(4) 20-monooxygenase 1; Leukotriene-B(4) omega-hydroxylase 1; EC 1.14.14.94; Phylloquinone omega-hydroxylase CYP4F2; EC 1.14.14.78
• Gene Name: CYP4F2
• UniProt ID: CP4F2_HUMAN
• EC Number: 1.14.14.1; 1.14.14.78; 1.14.14.79; 1.14.14.94
• Pfam ID: PF00067
• Sequence:
  MSQLSLSWLGLWPVAASPWLLLLLVGASWLLAHVLAWTYAFYDNCRRLRCFPQPPRRNWF
  WGHQGMVNPTEEGMRVLTQLVATYPQGFKVWMGPISPLLSLCHPDIIRSVINASAAIAPK
  DKFFYSFLEPWLGDGLLLSAGDKWSRHRRMLTPAFHFNILKPYMKIFNESVNIMHAKWQL
  LASEGSACLDMFEHISLMTLDSLQKCVFSFDSHCQEKPSEYIAAILELSALVSKRHHEIL
  LHIDFLYYLTPDGQRFRRACRLVHDFTDAVIQERRRTLPSQGVDDFLQAKAKSKTLDFID
  VLLLSKDEDGKKLSDEDIRAEADTFMFEGHDTTASGLSWVLYHLAKHPEYQERCRQEVQE
  LLKDREPKEIEWDDLAHLPFLTMCMKESLRLHPPVPVISRHVTQDIVLPDGRVIPKGIIC
  LISVFGTHHNPAVWPDPEVYDPFRFDPENIKERSPLAFIPFSAGPRNCIGQTFAMAEMKV
  VLALTLLRFRVLPDHTEPRRKPELVLRAEGGLWLRVEPLS
• Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids 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 (CPR; NADPH-ferrihemoprotein reductase). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of long- and very long-chain fatty acids. Displays high omega-hydroxylase activity toward polyunsaturated fatty acids (PUFAs). Participates in the conversion of arachidonic acid to omega-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure. Plays a role in the oxidative inactivation of eicosanoids, including both pro-inflammatory and anti-inflammatory mediators such as leukotriene B4 (LTB4), lipoxin A4 (LXA4), and several HETEs. Catalyzes omega-hydroxylation of 3-hydroxy fatty acids. Converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to omega-hydroxylated metabolites. Contributes to the degradation of very long-chain fatty acids (VLCFAs) by catalyzing successive omega-oxidations and chain shortening. Plays an important role in vitamin metabolism by chain shortening. Catalyzes omega-hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over alpha-tocopherols, thus promoting retention of alpha-tocopherols in tissues. Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation.
• Tissue Specificity: Liver. Also present in kidney: specifically expressed in the S2 and S3 segments of proximal tubules in cortex and outer medulla .
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Miscellaneous substrates (R-HSA-211958)
  Eicosanoids (R-HSA-211979)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) (R-HSA-2142816)
  Fatty acids (R-HSA-211935)
• BioCyc Pathway: MetaCyc:HS02675-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Warfarin	DMJYCVW	Approved	Cytochrome P450 4F2 (CYP4F2) increases the response to substance of Warfarin.	[13]
Acenocoumarol	DMH75KV	Approved	Cytochrome P450 4F2 (CYP4F2) affects the response to substance of Acenocoumarol.	[14]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phytonadione	DM8HDOL	Approved	Cytochrome P450 4F2 (CYP4F2) decreases the metabolism of Phytonadione.	[15]
Vitamin K	DMN6EZY	Investigative	Cytochrome P450 4F2 (CYP4F2) affects the metabolism of Vitamin K.	[17]
VITAMIN K2	DMJB3E1	Investigative	Cytochrome P450 4F2 (CYP4F2) affects the abundance of VITAMIN K2.	[18]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arachidonic acid	DMUOQZD	Investigative	Cytochrome P450 4F2 (CYP4F2) increases the hydroxylation of Arachidonic acid.	[16]
20-HETE	DM5BAJ9	Investigative	Cytochrome P450 4F2 (CYP4F2) increases the chemical synthesis of 20-HETE.	[16]

19 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 4F2 (CYP4F2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome P450 4F2 (CYP4F2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[1]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Cytochrome P450 4F2 (CYP4F2).	[4]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[5]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[6]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cytochrome P450 4F2 (CYP4F2).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cytochrome P450 4F2 (CYP4F2).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Cytochrome P450 4F2 (CYP4F2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[1]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Cytochrome P450 4F2 (CYP4F2).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cytochrome P450 4F2 (CYP4F2).	[4]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cytochrome P450 4F2 (CYP4F2).	[12]
2-chloro-5-nitro-N-phenylbenzamide	DMUGQIV	Investigative	2-chloro-5-nitro-N-phenylbenzamide decreases the expression of Cytochrome P450 4F2 (CYP4F2).	[7]

References

• [1] 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.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [5] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [6] 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.
• [7] CYP4F2 repression and a modified alpha-tocopherol (vitamin E) metabolism are two independent consequences of ethanol toxicity in human hepatocytes. Toxicol In Vitro. 2017 Apr;40:124-133.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Genistein, resveratrol, and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside induce cytochrome P450 4F2 expression through an AMP-activated protein kinase-dependent pathway. J Pharmacol Exp Ther. 2011 Apr;337(1):125-36.
• [10] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [13] CYP4F2 genetic variant alters required warfarin dose. Blood. 2008 Apr 15;111(8):4106-12. doi: 10.1182/blood-2007-11-122010. Epub 2008 Feb 4.
• [14] A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet. 2009 Oct 1;18(19):3758-68. doi: 10.1093/hmg/ddp309. Epub 2009 Jul 4.
• [15] Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study. Clin Ther. 2012 Apr;34(4):811-23. doi: 10.1016/j.clinthera.2012.02.009. Epub 2012 Mar 13.
• [16] Discovery of rubiarbonone C as a selective inhibitor of cytochrome P450 4F enzymes. Arch Toxicol. 2018 Nov;92(11):3325-3336. doi: 10.1007/s00204-018-2315-8. Epub 2018 Sep 27.
• [17] Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy. Pharmacogenet Genomics. 2009 Oct;19(10):781-9. doi: 10.1097/FPC.0b013e3283311347.
• [18] Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy. Thromb Res. 2015 May;135(5):861-6. doi: 10.1016/j.thromres.2015.02.019. Epub 2015 Feb 27.