Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome P450 4F3 (CYP4F3)
• Synonyms: EC 1.14.14.1; 20-hydroxyeicosatetraenoic acid synthase; 20-HETE synthase; CYPIVF3; Cytochrome P450-LTB-omega; Docosahexaenoic acid omega-hydroxylase CYP4F3; EC 1.14.14.79; Leukotriene-B(4) 20-monooxygenase 2; Leukotriene-B(4) omega-hydroxylase 2; EC 1.14.14.94
• Gene Name: CYP4F3
• UniProt ID: CP4F3_HUMAN
• EC Number: 1.14.14.1; 1.14.14.79; 1.14.14.94
• Pfam ID: PF00067
• Sequence:
  MPQLSLSSLGLWPMAASPWLLLLLVGASWLLARILAWTYTFYDNCCRLRCFPQPPKRNWF
  LGHLGLIHSSEEGLLYTQSLACTFGDMCCWWVGPWHAIVRIFHPTYIKPVLFAPAAIVPK
  DKVFYSFLKPWLGDGLLLSAGEKWSRHRRMLTPAFHFNILKPYMKIFNESVNIMHAKWQL
  LASEGSARLDMFEHISLMTLDSLQKCVFSFDSHCQEKPSEYIAAILELSALVTKRHQQIL
  LYIDFLYYLTPDGQRFRRACRLVHDFTDAVIQERRRTLPSQGVDDFLQAKAKSKTLDFID
  VLLLSKDEDGKKLSDEDIRAEADTFMFEGHDTTASGLSWVLYHLAKHPEYQERCRQEVQE
  LLKDREPKEIEWDDLAQLPFLTMCIKESLRLHPPVPAVSRCCTQDIVLPDGRVIPKGIIC
  LISVFGTHHNPAVWPDPEVYDPFRFDPKNIKERSPLAFIPFSAGPRNCIGQAFAMAEMKV
  VLGLTLLRFRVLPDHTEPRRKPELVLRAEGGLWLRVEPLS
• Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and their oxygenated derivatives (oxylipins). 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). May play a role in inactivation of pro-inflammatory and anti-inflammatory oxylipins during the resolution of inflammation ; [Isoform CYP4F3A]: Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of oxylipins in myeloid cells, displaying higher affinity for arachidonate metabolite leukotriene B4 (LTB4). Inactivates LTB4 via three successive oxidative transformations to 20-hydroxy-LTB4, then to 20-oxo-LTB4 and to 20-carboxy-LTB4. Has omega-hydroxylase activity toward long-chain fatty acid epoxides with preference for 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoate (EET) and 9,10-epoxyoctadecanoate. Omega-hydroxylates monohydroxy polyunsaturated fatty acids (PUFAs), including hydroxyeicosatetraenoates (HETEs) and hydroxyeicosapentaenoates (HEPEs), to dihydroxy compounds. Contributes to the degradation of saturated very long-chain fatty acids (VLCFAs) such as docosanoic acid, by catalyzing successive omega-oxidations to the corresponding dicarboxylic acid, thereby initiating chain shortening. Has low hydroxylase activity toward PUFAs ; [Isoform CYP4F3B]: Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of polyunsaturated fatty acids (PUFAs). Participates in the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure. Has high omega-hydroxylase activity toward other PUFAs, including eicosatrienoic acid (ETA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Can also catalyze the oxidation of the penultimate carbon (omega-1 oxidation) of PUFAs with lower efficiency. Contributes to the degradation of saturated very long-chain fatty acids (VLCFAs) such as docosanoic acid and hexacosanoic acid, by catalyzing successive omega-oxidations to the corresponding dicarboxylic acids, thereby initiating chain shortening. Omega-hydroxylates long-chain 3-hydroxy fatty acids, likely initiating the oxidative conversion to the corresponding 3-hydroxydicarboxylic fatty acids. Has omega-hydroxylase activity toward long-chain fatty acid epoxides with preference for 8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoate (EET) and 9,10-epoxyoctadecanoate.
• Tissue Specificity: .Selectively expressed in blood neutrophils and bone marrow cells. Coexpressed with CYP4F3B in prostate, ileum and trachea.; [Isoform CYP4F3B]: Selectively expressed in liver and kidney. It is also the predominant CYP4F isoform in trachea and tissues of the gastrointestinal tract.
• 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)
  Fatty acids (R-HSA-211935)
• BioCyc Pathway: MetaCyc:MONOMER66-44222

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arachidonic acid	DMUOQZD	Investigative	Cytochrome P450 4F3 (CYP4F3) increases the hydroxylation of Arachidonic acid.	[22]
20-HETE	DM5BAJ9	Investigative	Cytochrome P450 4F3 (CYP4F3) increases the chemical synthesis of 20-HETE.	[22]

21 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 4F3 (CYP4F3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome P450 4F3 (CYP4F3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytochrome P450 4F3 (CYP4F3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome P450 4F3 (CYP4F3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome P450 4F3 (CYP4F3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 4F3 (CYP4F3).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Cytochrome P450 4F3 (CYP4F3).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cytochrome P450 4F3 (CYP4F3).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cytochrome P450 4F3 (CYP4F3).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Cytochrome P450 4F3 (CYP4F3).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome P450 4F3 (CYP4F3).	[11]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Cytochrome P450 4F3 (CYP4F3).	[12]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cytochrome P450 4F3 (CYP4F3).	[13]
Urethane	DM7NSI0	Phase 4	Urethane affects the expression of Cytochrome P450 4F3 (CYP4F3).	[14]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Cytochrome P450 4F3 (CYP4F3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome P450 4F3 (CYP4F3).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytochrome P450 4F3 (CYP4F3).	[17]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Cytochrome P450 4F3 (CYP4F3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytochrome P450 4F3 (CYP4F3).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cytochrome P450 4F3 (CYP4F3).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cytochrome P450 4F3 (CYP4F3).	[21]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [2] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Human drug metabolism genes in parathion-and estrogen-treated breast cells. Int J Mol Med. 2007 Dec;20(6):875-81.
• [7] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [8] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] 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.
• [12] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [13] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Induction of CYP4F3 by benzene metabolites in human white blood cells in vivo in human promyelocytic leukemic cell lines and ex vivo in human blood neutrophils. Drug Metab Dispos. 2009 Feb;37(2):282-91.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [18] 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.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [21] 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.
• [22] 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.