Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHZ2GG2)

• DOT Name: Cytochrome P450 4F11 (CYP4F11)
• Synonyms: CYPIVF11; EC 1.14.14.1; 3-hydroxy fatty acids omega-hydroxylase CYP4F11; Docosahexaenoic acid omega-hydroxylase; EC 1.14.14.79; Long-chain fatty acid omega-monooxygenase; EC 1.14.14.80; Phylloquinone omega-hydroxylase CYP4F11; EC 1.14.14.78
• Gene Name: CYP4F11
• UniProt ID: CP4FB_HUMAN
• EC Number: 1.14.14.1; 1.14.14.78; 1.14.14.79; 1.14.14.80
• Pfam ID: PF00067
• Sequence:
  MPQLSLSWLGLGPVAASPWLLLLLVGGSWLLARVLAWTYTFYDNCRRLQCFPQPPKQNWF
  WGHQGLVTPTEEGMKTLTQLVTTYPQGFKLWLGPTFPLLILCHPDIIRPITSASAAVAPK
  DMIFYGFLKPWLGDGLLLSGGDKWSRHRRMLTPAFHFNILKPYMKIFNKSVNIMHDKWQR
  LASEGSARLDMFEHISLMTLDSLQKCVFSFESNCQEKPSEYIAAILELSAFVEKRNQQIL
  LHTDFLYYLTPDGQRFRRACHLVHDFTDAVIQERRCTLPTQGIDDFLKNKAKSKTLDFID
  VLLLSKDEDGKELSDEDIRAEADTFMFEGHDTTASGLSWVLYHLAKHPEYQEQCRQEVQE
  LLKDREPIEIEWDDLAQLPFLTMCIKESLRLHPPVPVISRCCTQDFVLPDGRVIPKGIVC
  LINIIGIHYNPTVWPDPEVYDPFRFDQENIKERSPLAFIPFSAGPRNCIGQAFAMAEMKV
  VLALTLLHFRILPTHTEPRRKPELILRAEGGLWLRVEPLGANSQ
• 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). Catalyzes with high efficiency the oxidation of the terminal carbon (omega-oxidation) of 3-hydroxy fatty acids, such as 3-hydroxyhexadecanoic and 3-hydroxyoctadecanoic acids, likely participating in the biosynthesis of long-chain 3-hydroxydicarboxylic acids. Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation. Metabolizes with low efficiciency fatty acids, including (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) and its oxygenated metabolite 8-hydroxyeicosatetraenoic acid (8-HETE). Catalyzes N- and O-demethylation of drugs such as erythromycin, benzphetamine, ethylmorphine, chlorpromazine, imipramine and verapamil. Catalyzes the oxidation of dialkylresorcinol 2.
• Tissue Specificity: Expressed mainly in human liver, followed by kidney, heart, and skeletal muscle.
• 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)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cytochrome P450 4F11 (CYP4F11).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytochrome P450 4F11 (CYP4F11).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome P450 4F11 (CYP4F11).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome P450 4F11 (CYP4F11).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cytochrome P450 4F11 (CYP4F11).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytochrome P450 4F11 (CYP4F11).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Cytochrome P450 4F11 (CYP4F11).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytochrome P450 4F11 (CYP4F11).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Cytochrome P450 4F11 (CYP4F11).	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Cytochrome P450 4F11 (CYP4F11).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cytochrome P450 4F11 (CYP4F11).	[11]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Cytochrome P450 4F11 (CYP4F11).	[3]
LG100268	DM41RK2	Discontinued in Phase 1	LG100268 increases the expression of Cytochrome P450 4F11 (CYP4F11).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytochrome P450 4F11 (CYP4F11).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cytochrome P450 4F11 (CYP4F11).	[14]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Investigative	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One decreases the expression of Cytochrome P450 4F11 (CYP4F11).	[3]
TTNPB	DMSABD0	Investigative	TTNPB decreases the expression of Cytochrome P450 4F11 (CYP4F11).	[3]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytochrome P450 4F11 (CYP4F11).	[12]

References

• [1] 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.
• [2] 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.
• [3] Gene regulation of CYP4F11 in human keratinocyte HaCaT cells. Drug Metab Dispos. 2010 Jan;38(1):100-7. doi: 10.1124/dmd.109.029025.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [10] 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.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] 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.
• [14] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.