{{Short description|Human enzyme}} {{Use dmy dates|date=March 2024}} {{Use American English|date=February 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox enzyme | name = Cytochrome P450 4F2 | AltNames = CYP4F2, 20-HETE synthase; 20-hydroxyeicosatetraenoic acid synthase; CYPIVF2; arachidonic acid omega-hydroxylase; cytochrome P450, family 4, subfamily F, polypeptide 2; cytochrome P450, subfamily IVF, polypeptide 2; cytochrome P450-LTB-omega; docosahexaenoic acid omega-hydroxylase; leucotriene-B<sub>4</sub> ω-hydroxylase; leukotriene-B(4) 20-monooxygenase 1; leukotriene-B(4) omega-hydroxylase 1; LTB4 omega-hydroxylase; phylloquinone omega-hydroxylase CYP4F2. | caption = Protein structure of cytochrome P450 4F2 (leukotriene-B<sub>4</sub> omega-hydroxylase 1) enzyme<ref name="RCSB Protein Data Bank-2022">{{cite web | url = https://www.rcsb.org/structure/AF_AFP78329F1 | title = Computed structure model of Cytochrome P450 4F2 | work = RCSB Protein Data Bank | id = AF_AFP78329F1 | date = 30 September 2022 | access-date = 26 November 2023 | archive-date = 26 November 2023 | archive-url = https://web.archive.org/web/20231126084822/https://www.rcsb.org/structure/AF_AFP78329F1 | url-status = live }} Structure of heme (represented as spheres) copied from {{PDB|6C94}} after alignment to AF_AFP78329F1.</ref> | EC_number = 1.14.14.94 | image = CYP4F2 AF AFP78329F1.png | CAS_number = 90119-11-2 }} {{Infobox gene}}'''Cytochrome P450 4F2''' ('''CYP4F2''') is a human enzyme belonging to the cytochrome P450 (CYP) superfamily. It plays a key role in regulating inflammation by inactivating leukotriene B<sub>4</sub>, a potent inflammatory mediator, and is clinically significant because genetic variations in its encoding gene (''CYP4F2'', part of a cluster of cytochrome P450 genes on chromosome 19) affect the dosing of the anticoagulant warfarin.

CYP enzymes function primarily as monooxygenases, adding a hydroxy group to their substrates. They are most highly expressed in the liver and are responsible for about 80% of oxidative metabolism and about 50% of the elimination of commonly used drugs in humans.

The primary substrate of CYP4F2 is leukotriene B<sub>4</sub> (LTB4), an eicosanoid inflammatory mediator. By hydroxylating LTB4 to its inactivated form 20-hydroxy-LTB4, the enzyme helps regulate inflammation. CYP4F2 also metabolizes other eicosanoids derived from arachidonic acid in white blood cells.

CYP4F2 also metabolizes certain fatty acids and fat-soluble vitamins, including vitamin E and vitamin K, and bioactivates prodrugs such as pafuramidine. Genetic variations in ''CYP4F2'' affect enzymatic activity, with implications for vitamin K bioavailability and the dosing of vitamin K antagonists like warfarin.

== Gene == {{See also|Introduction to genetics}}The cytochrome P450 4F2 protein is encoded by the ''CYP4F2'' gene in humans.<ref>{{cite web | title=Leukotriene-B4 omega-hydroxylase 1 - P78329 (CP4F2_HUMAN) | url=https://www.uniprot.org/uniprotkb/P78329/entry | website=UniProt | access-date=25 November 2023 | archive-date=25 November 2023 | archive-url=https://web.archive.org/web/20231125021248/https://www.uniprot.org/uniprotkb/P78329/entry | url-status=live }}</ref>

''CYP4F2'' is part of a cluster of cytochrome P450 genes located on chromosome 19, with another closely related gene, ''CYP4F11'', located approximately 16 kbp away.<ref name="entrez" /><ref name="omim" /> The CYP4F2 gene is composed of no fewer than 13 exons.<ref name="entrez" /><ref name="omim" /> The protein-coding sequence of the gene is from the second through the thirteenth exon, whereas the first exon contains a 49‑base‑pair segment forming part of the 5′ untranslated region,<ref name="omim" /> which makes the overall genomic organization of CYP4F2 very similar to that of CYP4F3.<ref name="pmid22706230">{{cite journal |vauthors=Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, Amet Y, Salaün JP |title=Human cytochrome P450 4F3: structure, functions, and prospects |journal=Drug Metabol Drug Interact |volume=27 |issue=2 |pages=63–71 |date=April 2012 |pmid=22706230 |doi=10.1515/dmdi-2011-0037 |s2cid=5258044 }}</ref>

Gene polymorphisms (variants) in ''CYP4F2'' affect liver mRNA levels and enzymatic activity of the protein encoded.<ref name="pmid28620303">{{cite journal | vauthors = Zhang JE, Klein K, Jorgensen AL, Francis B, Alfirevic A, Bourgeois S, Deloukas P, Zanger UM, Pirmohamed M | title = Effect of Genetic Variability in the ''CYP4F2'', ''CYP4F11'', and ''CYP4F12'' Genes on Liver mRNA Levels and Warfarin Response | journal = Frontiers in Pharmacology | volume = 8 | issue = | article-number = 323 | date = 2017 | pmid = 28620303 | pmc = 5449482 | doi = 10.3389/fphar.2017.00323 | doi-access = free }}</ref>

The analysis of the gene on a molecular level presents several difficulties: * ''CYP4F2'' is highly polymorphic, meaning that many genetic variants are present within the population; this makes it challenging to identify specific causal variants responsible for phenotypic effects or disease associations.<ref name="pmid37161313" /><ref name="pmid28620303" /> * ''CYP4F2'' is located within a cluster of genes of the CYP4F subfamily; these genes exhibit high homology, which can lead to difficulties in distinguishing between different subfamily members during genetic analysis, including distinguishing functional genes from pseudogenes within the cluster.<ref name="pmid18250228" /><ref name="pmid28620303" /> * The genes of the CYP4F subfamily tend to be closely linked on the chromosome and inherited together due to linkage disequilibrium, making it challenging to differentiate one gene's sequence from closely related genes or pseudogenes.<ref name="pmid37161313" /><ref name="pmid18250228" />

== Protein == The crystal structure of CYP4F2 has not been experimentally determined. Researchers have used homology modeling and molecular docking to construct theoretical models of the enzyme's structure and predict how it interacts with its substrates.<ref name="pmid36924012">{{cite journal |vauthors=Liang L, Zheng Q |title=Insights into the binding mechanism between α-TOH and CYP4F2: A homology modeling, molecular docking, and molecular dynamics simulation study |journal=J Cell Biochem |volume=124 |issue=4 |pages=573–585 |date=April 2023 |pmid=36924012 |doi=10.1002/jcb.30391 |s2cid=257580960 }}</ref>

== Species == The CYP4F subfamily is conserved across vertebrates, including mammals, birds, amphibians, and ray-finned fishes.<ref name="pmid22079551"/> However, ''CYP4F2'' is a human gene designation; other species have their own CYP4F genes with different numbers (for example, the mouse ortholog is ''Cyp4f14'').<ref name="pmid22079551"/><ref name="pmid22706230"/> The CYP4 family has also been identified in invertebrate groups such as ''Ascidiacea'', ''Echinoidea'', ''Gastropoda'', and ''Insecta'', though these organisms have distinct CYP4 subfamily members rather than direct CYP4F2 equivalents.<ref name="pmid22079551"/><ref name="pmid32869209">{{cite journal | vauthors = Liu J, Machalz D, Wolber G, Sorensen EJ, Bureik M | title = New Proluciferin Substrates for Human CYP4 Family Enzymes | journal = Applied Biochemistry and Biotechnology | volume = 193 | issue = 1 | pages = 218–237 | date = January 2021 | pmid = 32869209 | doi = 10.1007/s12010-020-03388-6 | s2cid = 221381798 }}</ref>

CYP4 enzymes from the same subfamily are often assumed to have similar functions across species, but this may not hold true, as CYP4 enzymes may have diverged in their biochemical properties and gene expression patterns over evolutionary time.<ref name="pmid22079551"/>

== Tissue and subcellular distribution == <!-- Tissue distribution --> In humans, ''CYP4F2'' is expressed in various tissues, including the liver, duodenum, small intestine, kidney, bone marrow, epididymis, and prostate,<ref name="The-Human-Protein Atlas-CYP4F2">{{cite web |title=CYP4F2 protein expression summary |work=The Human Protein Atlas |url=https://www.proteinatlas.org/ENSG00000186115-CYP4F2 |access-date=25 November 2023 |archive-date=25 November 2023 |archive-url=https://web.archive.org/web/20231125001701/https://www.proteinatlas.org/ENSG00000186115-CYP4F2 |url-status=live }}</ref> with the highest expression in the liver.<ref name="pmid12432928">{{cite journal | vauthors = Kikuta Y, Kusunose E, Kusunose M | title = Prostaglandin and leukotriene omega-hydroxylases | journal = Prostaglandins & Other Lipid Mediators | volume = 68 | pages = 345–362 | date = August 2002 | pmid = 12432928 | doi = 10.1016/s0090-6980(02)00039-4 }}</ref> ''CYP4F2'' expression can be influenced by various factors, such as genetic variations, dietary intake, drug interactions, and inflammatory conditions.<ref name="pmid34884595">{{cite journal | vauthors = Grangeon A, Clermont V, Barama A, Gaudette F, Turgeon J, Michaud V | title = Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics | journal = International Journal of Molecular Sciences | volume = 22 | issue = 23 | article-number = 12791 | date = November 2021 | pmid = 34884595 | pmc = 8657875 | doi = 10.3390/ijms222312791 | doi-access = free }}</ref>

<!-- Subcellular distribution --> The CYP4F2 protein localizes to the endoplasmic reticulum (ER) membrane.<ref name="entrez" /><ref name="pmid25370453"/> Specifically, CYP4F2 resides in the smooth endoplasmic reticulum, where it interacts with electron transfer partners such as NADPH-cytochrome P450 reductase and cytochrome b<sub>5</sub>.<ref name="omim" /><ref name="entrez" /> The Human Protein Atlas has not yet completed experimental immunofluorescence imaging for CYP4F2 in its cell line panel.<ref name="subcellular">{{cite web | title = CYP4F2 Subcellular RNA expression | work = The Human Protein Atlas | url = https://www.proteinatlas.org/ENSG00000186115-CYP4F2/subcellular | access-date = 25 November 2023 | archive-date = 25 November 2023 | archive-url = https://web.archive.org/web/20231125025809/https://www.proteinatlas.org/ENSG00000186115-CYP4F2/subcellular | url-status = live }}</ref>

== Function == ===The cytochrome P450 superfamily=== {{See also|Cytochrome P450}} CYP4F2 is a member of the cytochrome P450 (CYP) superfamily, a group of hemoprotein enzymes bound to cell membranes that are most abundant in the liver.<ref name="entrez" /><ref name="pmid34884615">{{cite journal |vauthors=Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, Huai C, Shen L, Zhang N, He L, Qin S |title=Cytochrome P450 Enzymes and Drug Metabolism in Humans |journal=Int J Mol Sci |volume=22 |issue=23 |date=November 2021 |article-number=12808 |pmid=34884615 |pmc=8657965 |doi=10.3390/ijms222312808 |doi-access=free}}</ref> CYP enzymes are involved in cellular metabolism, hormone synthesis, and cholesterol metabolism, and are responsible for about 80% of oxidative metabolism and about 50% of drug elimination in humans.<ref name="pmid34884615"/><ref name="pmid24523112">{{cite book |title=Enzyme Kinetics in Drug Metabolism |chapter=Enzyme Kinetics of Oxidative Metabolism: Cytochromes P450 |date=2014 |series=Methods in Molecular Biology |volume=1113 |pages=149–166 |doi=10.1007/978-1-62703-758-7_8 |issn=1940-6029 |pmid=24523112|isbn=978-1-62703-757-0 | vauthors = Korzekwa K |publisher=Humana Press }}</ref> CYP enzymes are frequently targeted in drug development due to their roles in vascular function, sex hormone biosynthesis, and inflammatory response.<ref name="pmid37793784">{{cite journal |vauthors=Guengerich FP |title=Cytochrome P450 enzymes as drug targets in human disease |journal=Drug Metab Dispos |date=October 2023 |volume=52 |issue=6 |pages=493–497 |pmid=37793784 |doi=10.1124/dmd.123.001431 |s2cid=263675700 |doi-access=free |pmc=11114603 }}</ref><ref name="pmid33112969">{{cite journal |vauthors=Stipp MC, Acco A |title=Involvement of cytochrome P450 enzymes in inflammation and cancer: a review |journal=Cancer Chemother Pharmacol |volume=87 |issue=3 |pages=295–309 |date=March 2021 |pmid=33112969 |doi=10.1007/s00280-020-04181-2 |s2cid=225080314 }}</ref>

===The CYP4F subfamily=== The CYP4F subfamily of CYP enzymes exhibits diverse metabolic specificities, but is characterized by the ω-hydroxylation of very long-chain fatty acids (VLCFA), eicosanoids, lipophilic (fat-soluble) vitamins, and hydroxyeicosatetraenoic acids (HETEs).<ref name="pmid22079551">{{cite journal | vauthors = Kirischian NL, Wilson JY | title = Phylogenetic and functional analyses of the cytochrome P450 family 4 | journal = Molecular Phylogenetics and Evolution | volume = 62 | issue = 1 | pages = 458–471 | date = January 2012 | pmid = 22079551 | doi = 10.1016/j.ympev.2011.10.016 | bibcode = 2012MolPE..62..458K }}</ref> The cytochrome P450 4F2 protein is an enzyme also known as "leukotriene-B<sub>4</sub> ω-hydroxylase 1", because it starts the process of inactivating and degrading leukotriene B<sub>4</sub> (LTB4), a potent mediator of inflammation, by ω-hydroxylating it to 20-hydroxy-LTB4.<ref name="entrez">{{NCBI RefSeq|title=CYP4F2 cytochrome P450 family 4 subfamily F member 2|url=https://www.ncbi.nlm.nih.gov/gene/8529|access-date=30 November 2020|publisher=National Center for Biotechnology Information|quote=This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. The enzyme starts the process of inactivating and degrading leukotriene B<sub>4</sub>, a potent mediator of inflammation. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this subfamily, CYP4F11, is approximately 16 kbp away.|archive-date=10 April 2021|archive-url=https://web.archive.org/web/20210410062747/https://www.ncbi.nlm.nih.gov/gene/8529|url-status=live}}{{PD-notice}}</ref>

CYP4F2 and CYP4F3 catalyze the omega-hydroxylation of pro- and anti-inflammatory leukotrienes, modulating their biological activities.<ref name="pmid22706230"/><ref name="pmid22079551"/> Other CYP4F subfamily members have related but distinct roles: CYP4F8 and CYP4F12 metabolize prostaglandins and arachidonic acid, while CYP4F11 and CYP4F12 can also hydroxylate xenobiotics such as certain drugs.<ref name="pmid31480463">{{cite journal |vauthors=Jarrar YB, Lee SJ |title=Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications |journal=Int J Mol Sci |volume=20 |issue=17 |date=August 2019 |page=4274 |pmid=31480463 |pmc=6747359 |doi=10.3390/ijms20174274 |doi-access=free}}</ref><ref name="pmid22079551" /> The related CYP4X and CYP4Z subfamilies remain classified as "orphan" enzymes with incompletely characterized physiological functions.<ref name="pmid36958639">{{cite journal |vauthors=Zhou J, Li D, Xu J, Zheng Q, Xu W |title=Exploring human CYP4 enzymes: Physiological roles, function in diseases and focus on inhibitors |journal=Drug Discov Today |volume=28 |issue=5 |article-number=103560 |date=May 2023 |pmid=36958639 |doi=10.1016/j.drudis.2023.103560 }}</ref>

The CYP4F subfamily plays a role in the development of cancer. Enzymes such as CYP4F2 and CYP4F3B convert arachidonic acid into 20-Hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid metabolite of arachidonic acid. This metabolite impacts the progression of tumors, the formation of new blood vessels (angiogenesis), and the regulation of blood pressure in blood vessels and kidneys.<ref name="pmid33112969"/><ref name="pmid34594219">{{cite journal |vauthors=Ni KD, Liu JY |title=The Functions of Cytochrome P450 ω-hydroxylases and the Associated Eicosanoids in Inflammation-Related Diseases |journal=Front Pharmacol |volume=12 |issue= |article-number=716801 |date=2021 |pmid=34594219 |pmc=8476763 |doi=10.3389/fphar.2021.716801 |doi-access=free}}</ref>

===CYP4F2 within the subfamily=== Beyond its role in degrading LTB4, CYP4F2 metabolizes various endogenous substrates including fatty acids, eicosanoids, and fat-soluble vitamins.<ref name="CYP4F2-Gene-Uniprot">{{cite web |url=https://www.uniprot.org/uniprot/P78329#function |title=CYP4F2 Gene - Function |website=UniProt |access-date=3 July 2020 |archive-date=6 August 2020 |archive-url=https://web.archive.org/web/20200806164948/https://www.uniprot.org/uniprot/P78329#function |url-status=live }}</ref> It regulates the bioavailability of vitamin E by catalyzing the rate-limiting step in vitamin E catabolism,<ref name="pmid26981194">{{cite journal | vauthors = Schmölz L, Birringer M, Lorkowski S, Wallert M | title = Complexity of vitamin E metabolism | journal = World Journal of Biological Chemistry | volume = 7 | issue = 1 | pages = 14–43 | date = February 2016 | pmid = 26981194 | pmc = 4768118 | doi = 10.4331/wjbc.v7.i1.14 | doi-access = free }}</ref><ref name="pmid25370453"/> and also regulates the bioavailability of vitamin K, a co-factor required for blood clotting.<ref name="pmid33080066"/>

Gene polymorphisms in ''CYP4F2'' affect enzymatic activity.<ref name="pmid33080066"/> Variations that alter vitamin K bioavailability also affect the dosing of vitamin K antagonists such as warfarin,<ref name="pmid33080066">{{cite journal | vauthors = Asiimwe IG, Zhang EJ, Osanlou R, Jorgensen AL, Pirmohamed M | title = Warfarin dosing algorithms: A systematic review | journal = British Journal of Clinical Pharmacology | volume = 87 | issue = 4 | pages = 1717–1729 | date = April 2021 | pmid = 33080066 | pmc = 8056736 | doi = 10.1111/bcp.14608 }}</ref><ref name="pmid37273173">{{cite journal | vauthors = Zhao Z, Zhao F, Wang X, Liu D, Liu J, Zhang Y, Hu X, Zhao M, Tian C, Dong S, Jin P | title = Genetic Factors Influencing Warfarin Dose in Han Chinese Population: A Systematic Review and Meta-Analysis of Cohort Studies | journal = Clinical Pharmacokinetics | volume = 62 | issue = 6 | pages = 819–833 | date = June 2023 | pmid = 37273173 | doi = 10.1007/s40262-023-01258-y | s2cid = 259073998 }}</ref><ref name="pmid33346393">{{cite journal | vauthors = Sridharan K, Sivaramakrishnan G | title = A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 46 | issue = 3 | pages = 640–648 | date = June 2021 | pmid = 33346393 | doi = 10.1111/jcpt.13334 | s2cid = 229342467 | doi-access = }}</ref> coumarin, or acenocoumarol.<ref name="PkarmGKB-Very-Important">{{cite web |url=https://www.pharmgkb.org/vip/PA166169424 |title=Very Important Pharmacogene: CYP4F2 |work=PharmGKB |publisher=Stanford University |access-date=3 July 2020 |archive-date=5 July 2020 |archive-url=https://web.archive.org/web/20200705155759/https://www.pharmgkb.org/vip/PA166169424 |url-status=live }}</ref><ref name="pmid30506689">{{cite journal | vauthors = Danese E, Raimondi S, Montagnana M, Tagetti A, Langaee T, Borgiani P, Ciccacci C, Carcas AJ, Borobia AM, Tong HY, Dávila-Fajardo C, Rodrigues Botton M, Bourgeois S, Deloukas P, Caldwell MD, Burmester JK, Berg RL, Cavallari LH, Drozda K, Huang M, Zhao LZ, Cen HJ, Gonzalez-Conejero R, Roldan V, Nakamura Y, Mushiroda T, Gong IY, Kim RB, Hirai K, Itoh K, Isaza C, Beltrán L, Jiménez-Varo E, Cañadas-Garre M, Giontella A, Kringen MK, Haug KB, Gwak HS, Lee KE, Minuz P, Lee MT, Lubitz SA, Scott S, Mazzaccara C, Sacchetti L, Genç E, Özer M, Pathare A, Krishnamoorthy R, Paldi A, Siguret V, Loriot MA, Kutala VK, Suarez-Kurtz G, Perini J, Denny JC, Ramirez AH, Mittal B, Rathore SS, Sagreiya H, Altman R, Shahin MH, Khalifa SI, Limdi NA, Rivers C, Shendre A, Dillon C, Suriapranata IM, Zhou HH, Tan SL, Tatarunas V, Lesauskaite V, Zhang Y, Maitland-van der Zee AH, Verhoef TI, de Boer A, Taljaard M, Zambon CF, Pengo V, Zhang JE, Pirmohamed M, Johnson JA, Fava C | title = Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals | journal = Clinical Pharmacology and Therapeutics | volume = 105 | issue = 6 | pages = 1477–1491 | date = June 2019 | pmid = 30506689 | pmc = 6542461 | doi = 10.1002/cpt.1323 }}</ref>

CYP4F2 also regulates the bioactivation of certain drugs, such as the anti-parasitic prodrug pafuramidine, by catalyzing the initial oxidative O-demethylation in human liver and intestinal microsomes to produce its active form, furamidine.<ref name="pmid25370453"/><ref name="pmid23561006">{{cite journal |vauthors=Soeiro MN, Werbovetz K, Boykin DW, Wilson WD, Wang MZ, Hemphill A |title=Novel amidines and analogues as promising agents against intracellular parasites: a systematic review |journal=Parasitology |volume=140 |issue=8 |pages=929–51 |date=July 2013 |pmid=23561006 |pmc=3815587 |doi=10.1017/S0031182013000292 |url=}}</ref><ref name="pmid23360144">{{cite journal |vauthors=Ortiz de Montellano PR |title=Cytochrome P450-activated prodrugs |journal=Future Med Chem |volume=5 |issue=2 |pages=213–28 |date=February 2013 |pmid=23360144 |pmc=3697796 |doi=10.4155/fmc.12.197 |url=}}</ref> The enzyme additionally plays a role in renal water homeostasis through its production of 20-HETE.<ref name="pmid10660572">{{cite journal | vauthors = Lasker JM, Chen WB, Wolf I, Bloswick BP, Wilson PD, Powell PK | title = Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 6 | pages = 4118–4126 | date = February 2000 | pmid = 10660572 | doi = 10.1074/jbc.275.6.4118 | s2cid = 41956184 | doi-access = free }}</ref>

===Metabolism of leukotriene B<sub>4</sub>=== ==== Biosynthesis of leukotriene B<sub>4</sub> from arachidonic acid ==== Leukotriene B<sub>4</sub> (LTB4) is a type of lipid mediator that belongs to the family of leukotrienes, which are derived from arachidonic acid by the action of 5-lipoxygenase (5-LOX).<ref name="pmid11368003">{{cite journal | vauthors = Yokomizo T, Izumi T, Shimizu T | title = Leukotriene B4: metabolism and signal transduction | journal = Archives of Biochemistry and Biophysics | volume = 385 | issue = 2 | pages = 231–241 | date = January 2001 | pmid = 11368003 | doi = 10.1006/abbi.2000.2168 }}</ref>

Arachidonic acid is a polyunsaturated fatty acid that is present in the phospholipids of cell membranes. It can be released from the membrane by the action of phospholipase A2, a peripheral membrane protein, which is activated by stimuli such as hormones, cytokines, growth factors and stress. Arachidonic acid can then be metabolized by three major pathways: the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway, and the cytochrome P450 (CYP) pathway.<ref name="pmid31357612">{{cite journal | vauthors = Wang T, Fu X, Chen Q, Patra JK, Wang D, Wang Z, Gai Z | title = Arachidonic Acid Metabolism and Kidney Inflammation | journal = International Journal of Molecular Sciences | volume = 20 | issue = 15 | page = 3683 | date = July 2019 | pmid = 31357612 | pmc = 6695795 | doi = 10.3390/ijms20153683 | doi-access = free | bibcode = 2019IJMSc..20.3683W }}</ref> These pathways produce different types of lipid mediators, which are collectively called eicosanoids.<ref name="pmid11368003"/>

Eicosanoids are a group of bioactive molecules that have diverse and potent effects on physiological and pathological processes such as inflammation, immunity, pain, fever, blood pressure, blood clotting, reproduction and cancer. There are multiple types of eicosanoids, such as prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids (HETEs), and so on.<ref name="pmid32808658">{{cite journal |vauthors=Calder PC |title=Eicosanoids |journal=Essays Biochem |volume=64 |issue=3 |pages=423–441 |date=September 2020 |pmid=32808658 |doi=10.1042/EBC20190083 |s2cid=221162836 |url=https://eprints.soton.ac.uk/443186/1/Calder_Eicosanoids_Revised_Clean.pdf |archive-date=25 November 2023 |access-date=30 November 2023 |archive-url=https://web.archive.org/web/20231125021851/https://eprints.soton.ac.uk/443186/1/Calder_Eicosanoids_Revised_Clean.pdf |url-status=live }}</ref>

Leukotriene B<sub>4</sub> (LTB4) is one of the eicosanoids that is produced by the LOX pathway. It is synthesized from arachidonic acid by the sequential actions of 5-LOX, 5-lipoxygenase-activating protein, and leukotriene A4 hydrolase.<ref name="pmid11368003"/>

LTB4 is produced by activated innate immune cells, such as neutrophils, macrophages and mast cells.<ref name="pmid18797182">{{cite journal | vauthors = Ohnishi H, Miyahara N, Gelfand EW | title = The role of leukotriene B(4) in allergic diseases | journal = Allergology International | volume = 57 | issue = 4 | pages = 291–298 | date = December 2008 | pmid = 18797182 | doi = 10.2332/allergolint.08-RAI-0019 | doi-access = free }}</ref><ref name="pmid11368003" /> It induces the activation of polymorphonuclear leukocytes, monocytes and fibroblasts, the production of superoxide and the release of cytokines to attract neutrophils.<ref name="pmid16926051">{{cite journal | vauthors = Kalsotra A, Strobel HW | title = Cytochrome P450 4F subfamily: at the crossroads of eicosanoid and drug metabolism | journal = Pharmacology & Therapeutics | volume = 112 | issue = 3 | pages = 589–611 | date = December 2006 | pmid = 16926051 | doi = 10.1016/j.pharmthera.2006.03.008 }}</ref><ref name="pmid17341693">{{cite journal | vauthors = Stec DE, Roman RJ, Flasch A, Rieder MJ | title = Functional polymorphism in human CYP4F2 decreases 20-HETE production | journal = Physiological Genomics | volume = 30 | issue = 1 | pages = 74–81 | date = June 2007 | pmid = 17341693 | doi = 10.1152/physiolgenomics.00003.2007 }}</ref><ref name="pmid18433732">{{cite journal | vauthors = Hardwick JP | title = Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases | journal = Biochemical Pharmacology | volume = 75 | issue = 12 | pages = 2263–2275 | date = June 2008 | pmid = 18433732 | doi = 10.1016/j.bcp.2008.03.004 }}</ref>

====The role of leukotriene B<sub>4</sub> in inflammatory response==== LTB4 plays a key role in the initiation and maintenance of inflammation, as it can recruit and activate immune cells such as neutrophils, macrophages, mast cells, monocytes and fibroblasts. LTB4 also stimulates the production of reactive oxygen species, cytokines, chemokines and cell adhesion molecules, which further amplify the inflammatory response.<ref name="pmid9608670">{{cite journal | vauthors = Crooks SW, Stockley RA | title = Leukotriene B4 | journal = The International Journal of Biochemistry & Cell Biology | volume = 30 | issue = 2 | pages = 173–178 | date = February 1998 | pmid = 9608670 | doi = 10.1016/s1357-2725(97)00123-4 | s2cid = 45983006 }}</ref><ref name="pmid23988515">{{cite journal | vauthors = Le Bel M, Brunet A, Gosselin J | title = Leukotriene B4, an endogenous stimulator of the innate immune response against pathogens | journal = Journal of Innate Immunity | volume = 6 | issue = 2 | pages = 159–168 | date = 2014 | pmid = 23988515 | pmc = 6741447 | doi = 10.1159/000353694 }}</ref>

==== Inactivation of leukotriene B<sub>4</sub> by CYP4F2 ==== thumb|320px|Hydroxylation of Leukotriene B<sub>4</sub> catalyzed by CYP4F2

Excessive or prolonged inflammation can be harmful to the host, as it can cause tissue damage and chronic diseases, so that the inflammatory process must be tightly regulated and resolved in a timely manner. One of the mechanisms that contributes to the resolution of inflammation is the enzymatic inactivation and degradation of LTB4 by the cytochrome P450 (CYP) family of enzymes. CYP enzymes are mainly expressed in the liver, but they can also be found in other tissues, such as the lungs, kidneys, intestines, and skin.<ref name="pmid34944517">{{cite journal | vauthors = Das UN | title = Essential Fatty Acids and Their Metabolites in the Pathobiology of Inflammation and Its Resolution | journal = Biomolecules | volume = 11 | issue = 12 | page = 1873 | date = December 2021 | pmid = 34944517 | pmc = 8699107 | doi = 10.3390/biom11121873 | doi-access = free }}</ref><ref name="pmid32439596">{{cite journal | vauthors = He R, Chen Y, Cai Q | title = The role of the LTB4-BLT1 axis in health and disease | journal = Pharmacological Research | volume = 158 | issue = | article-number = 104857 | date = August 2020 | pmid = 32439596 | doi = 10.1016/j.phrs.2020.104857 | s2cid = 218834028 }}</ref>

Among the CYP enzymes, CYP4F2 is the most important for the metabolism of LTB4.<ref name="pmid31480463"/><ref name="omim" /><ref name="pmid9799565">{{cite journal | vauthors = Jin R, Koop DR, Raucy JL, Lasker JM | title = Role of human CYP4F2 in hepatic catabolism of the proinflammatory agent leukotriene B4 | journal = Archives of Biochemistry and Biophysics | volume = 359 | issue = 1 | pages = 89–98 | date = November 1998 | pmid = 9799565 | doi = 10.1006/abbi.1998.0880 }}</ref> It catalyzes the omega-hydroxylation of LTB4 as the first step of inactivation, converting it to 20-hydroxy-LTB4, which has much lower biological activity.<ref name="pmid9675028"/> CYP4F2 then converts 20-hydroxy-LTB4 to 20-oxo-LTB4 and then to 20-carboxy-LTB4,<ref name="pmid9675028">{{cite journal | vauthors = Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M | title = Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3) | journal = Archives of Biochemistry and Biophysics | volume = 355 | issue = 2 | pages = 201–205 | date = July 1998 | pmid = 9675028 | doi = 10.1006/abbi.1998.0724 }}</ref> which are both inactive and can be excreted from the body.<ref name="pmid26233909">{{cite book |vauthors=Johnson AL, Edson KZ, Totah RA, Rettie AE |title=Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer |chapter=Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer |series=Adv Pharmacol |volume=74 |pages=223–62 |date=2015 |publisher=Academic Press |pmid=26233909 |pmc=4667791 |doi=10.1016/bs.apha.2015.05.002 |isbn=978-0-12-803119-3 }}</ref><ref name="pmid22706230"/>

=== Fatty acid ω-hydroxylation === {{See also|Cytochrome P450 omega hydroxylase}} CYP4F2 belongs to cytochrome P450 omega hydroxylase set of enzymes that catalyze the addition of a hydroxy functional group (−OH) to a molecule of the fatty acid substrate. Specifically, CYP4F2 performs ω-hydroxylation of fatty acids, which means that the functional group is added to the ω- or (ω-1)-C atom. In the context of fatty acids, the ω (omega) atom refers to the carbon atom (C) at the end of the hydrocarbon chain, furthest from the carboxyl group, so that the ω- or (ω-1)-C atom refers to the last carbon atom or the second-to-last carbon atom in the hydrocarbon chain of the fatty acid: the hydroxy group (−OH) is added to one of these atoms during the ω-hydroxylation process.<ref name="pmid26233909"/>

The enzymes which are members of the CYP4A and CYP4F sub-families, including CYP4F2, may ω-hydroxylate and thereby reduce the activity of fatty acid metabolites of arachidonic acid such as LTB4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins. These enzymatic reactions lead to the production of metabolites involved in regulating inflammatory and vascular responses in animals and humans.<ref name="pmid9675028"/><ref name="pmid18433732"/> By reducing the activity of these fatty acid metabolites, ω-hydroxylation plays a role in dampening inflammatory pathways and maintaining immune system balance.<ref name="pmid18433732" />

Certain single-nucleotide polymorphisms (SNPs) in the ''CYP4F2'' have been associated with human diseases like Crohn's disease<ref name="pmid24406470">{{cite journal | vauthors = Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, Amre DK | title = Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease | journal = Gastroenterology | volume = 146 | issue = 4 | pages = 929–931 | date = April 2014 | pmid = 24406470 | doi = 10.1053/j.gastro.2013.12.034 | url = https://zenodo.org/record/896397 | access-date = 3 July 2020 | url-status = live | archive-url = https://web.archive.org/web/20200703195214/https://zenodo.org/record/896397 | archive-date = 3 July 2020 | doi-access = free }}</ref><ref name="pmid21187935">{{cite journal | vauthors = Costea I, Mack DR, Israel D, Morgan K, Krupoves A, Seidman E, Deslandres C, Lambrette P, Grimard G, Levy E, Amre DK | title = Genes involved in the metabolism of poly-unsaturated fatty-acids (PUFA) and risk for Crohn's disease in children & young adults | journal = PLOS ONE | volume = 5 | issue = 12 | article-number = e15672 | date = December 2010 | pmid = 21187935 | pmc = 3004960 | doi = 10.1371/journal.pone.0015672 | doi-access = free | bibcode = 2010PLoSO...515672C }}</ref> and Coeliac disease.<ref name="pmid18433732" /><ref name="pmid16835590">{{cite journal | vauthors = Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C | title = A functional candidate screen for coeliac disease genes | journal = European Journal of Human Genetics | volume = 14 | issue = 11 | pages = 1215–1222 | date = November 2006 | pmid = 16835590 | doi = 10.1038/sj.ejhg.5201687 | doi-access = free }}</ref><ref name="pmid22706230"/> These genetic variations may impact the function or expression level of the enzyme, influencing its ability to perform ω-hydroxylation reactions effectively.<ref name="pmid22706230"/>

The CYP4F2 enzyme also catalyzes ω-hydroxylation of 3-hydroxy fatty acids.<ref name="pmid18065749">{{cite journal | vauthors = Dhar M, Sepkovic DW, Hirani V, Magnusson RP, Lasker JM | title = Omega oxidation of 3-hydroxy fatty acids by the human CYP4F gene subfamily enzyme CYP4F11 | journal = Journal of Lipid Research | volume = 49 | issue = 3 | pages = 612–624 | date = March 2008 | pmid = 18065749 | doi = 10.1194/jlr.M700450-JLR200 | s2cid = 28835933 | doi-access = free }}</ref> It converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to ω-hydroxylated metabolites.<ref name="pmid15145985">{{cite journal | vauthors = Le Quéré V, Plée-Gautier E, Potin P, Madec S, Salaün JP | title = Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides | journal = Journal of Lipid Research | volume = 45 | issue = 8 | pages = 1446–1458 | date = August 2004 | pmid = 15145985 | doi = 10.1194/jlr.M300463-JLR200 | s2cid = 6065789 | doi-access = free }}</ref> By ω-hydroxylating 3-hydroxy fatty acids, the enzyme contributes to the modification of these molecules, which can have implications for their signaling functions in cellular processes. The production of ω-hydroxylated metabolites from monoepoxides derived from linoleic acid leukotoxin and isoleukotoxin helps regulate inflammation by reducing their activity as pro-inflammatory mediators.<ref name="pmid18065749" /><ref name="pmid15145985" />

The enzyme also contributes to the degradation of VLCFAs by catalyzing successive ω-oxidations and chain shortening. This enzymatic activity ensures efficient breakdown and clearance of these fatty acids, preventing accumulation that could lead to metabolic imbalances or contribute to disease pathology.<ref name="pmid16547005">{{cite journal | vauthors = Sanders RJ, Ofman R, Duran M, Kemp S, Wanders RJ | title = Omega-oxidation of very long-chain fatty acids in human liver microsomes. Implications for X-linked adrenoleukodystrophy | journal = The Journal of Biological Chemistry | volume = 281 | issue = 19 | pages = 13180–13187 | date = May 2006 | pmid = 16547005 | doi = 10.1074/jbc.M513481200 | doi-access = free | s2cid = 26142051 }}</ref><ref name="pmid18182499">{{cite journal | vauthors = Sanders RJ, Ofman R, Dacremont G, Wanders RJ, Kemp S | title = Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids | journal = FASEB Journal | volume = 22 | issue = 6 | pages = 2064–2071 | date = June 2008 | pmid = 18182499 | doi = 10.1096/fj.07-099150 | doi-access = free | url = https://biblio.ugent.be/publication/745741 | access-date = 3 July 2020 | url-status = live | hdl = 1854/LU-745741 | s2cid = 36659127 | archive-url = https://web.archive.org/web/20200703214150/https://biblio.ugent.be/publication/745741 | archive-date = 3 July 2020 | hdl-access = free }}</ref>

=== Fatty acid chain shortening === The process of chain shortening refers to the modification of a fatty acid molecule by removing carbon atoms from its chain. Fatty acids are organic molecules consisting of a long hydrocarbon chain, typically with an even number of carbon (C) atoms. These chains can vary in length, and their length affects their biological activities. CYP4F2 acts on fatty acids and introduces oxidative reactions that lead to the removal of carbon atoms from the chain. This process is often accompanied by the addition of oxygen to the fatty acid molecule, resulting in the formation of metabolites or breakdown products. By shortening the fatty acid chains, the CYP4F2 enzyme plays a role in vitamin metabolism. This process can affect the bioavailability, transportation, and utilization of certain fat-soluble vitamins in the body. The specific impact of chain shortening on vitamin metabolism may vary depending on the specific fatty acid and vitamin involved. This process is essential for maintaining lipid homeostasis and regulating biological activities influenced by fatty acids.<ref name="pmid25370453">{{cite journal | vauthors = Alvarellos ML, Sangkuhl K, Daneshjou R, Whirl-Carrillo M, Altman RB, Klein TE | title = PharmGKB summary: very important pharmacogene information for CYP4F2 | journal = Pharmacogenetics and Genomics | volume = 25 | issue = 1 | pages = 41–47 | date = January 2015 | pmid = 25370453 | pmc = 4261059 | doi = 10.1097/FPC.0000000000000100 }}</ref>

Fatty acid chain shortening by CYP4F2 is performed by their α-, β-, and ω-oxidation, with the preferred pathway being the β-oxidation in the mitochondria and peroxisomes. VLCFAs cannot be β-oxidized. The number of carbon atoms in the chains of such acids exceeds 22. Such chains must be shortened before being oxidized by mitochondria. The CYP4F2 enzyme is involved in catalyzing the ω-oxidation and chain shortening of such acids.<ref name="pmid25370453"/> CYP4F2 also mediates the metabolism of long-chain polyunsaturated fatty acids (PUFAs), such as ω−3 and ω−6 fatty acids, which are required for physiological processes such as brain development, inflammation modulation, and cardiovascular health.<ref name="pmid25370453" />

=== Metabolism of vitamins === The enzyme plays its role in metabolism of vitamins E and K by chain shortening,<ref name="Stipanuk-2018">{{cite book |title=Biochemical, Physiological, and Molecular Aspects of Human Nutrition - E-Book |isbn=978-0-323-40213-2 |publisher=Elsevier Health Sciences |edition=4th |year=2018 | vauthors = Stipanuk MH, Caudill MA |url=https://books.google.com/books?id=fEpVDwAAQBAJ&pg=PA711 |access-date=4 July 2020 |archive-date=15 July 2020 |archive-url=https://web.archive.org/web/20200715221917/https://books.google.com/books?id=fEpVDwAAQBAJ&pg=PA711 |url-status=live}}</ref><ref name="Bohm-2018">{{cite book |title=Vitamin E | vauthors = Böhm V |year=2018 |url=https://www.mdpi.com/books/pdfview/book/635 |isbn=978-3-03842-906-7 |page=60 | publisher = MDPI - Multidisciplinary Digital Publishing Institute | doi = 10.3390/books978-3-03842-906-7 |access-date=4 July 2020 |archive-date=5 July 2020 |archive-url=https://web.archive.org/web/20200705202204/https://www.mdpi.com/books/pdfview/book/635 |url-status=live | doi-access = free }}</ref> i.e., by reducing the number of carbon atoms in certain hydrocarbon chains of the molecules of the vitamin, depending on a particular vitamin molecule. This process is also known as ω-hydroxylation, because it involves adding a hydroxy group (-OH) to the last carbon atom (omega position) of the chain. This makes the vitamin molecule more polar (increase chemical polarity) and less stable, and facilitates its further degradation by other enzymes.<ref name="Snyder-2012">{{cite book | vauthors = Snyder F |url=https://books.google.com/books?id=mqLzBwAAQBAJ&pg=PA44 |title=Lipid metabolism in mammals |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-1-4684-2832-2 |page=44 |access-date=12 July 2020 |archive-url=https://web.archive.org/web/20200808033545/https://books.google.com/books?id=mqLzBwAAQBAJ&pg=PA44 |archive-date=8 August 2020 |url-status=live}}</ref><ref name="Numa-1984">{{cite book |url=https://books.google.com/books?id=PlfcoPVDb6YC&pg=PA132 |title=Fatty Acid Metabolism and its Regulation |date=January 1984 |publisher=Elsevier |isbn=0-444-80528-1 | veditors = Numa S |page=132 |access-date=12 July 2020 |archive-url=https://web.archive.org/web/20210707165134/https://books.google.com/books?id=PlfcoPVDb6YC&pg=PA132 |archive-date=7 July 2021 |url-status=live}}</ref>

CYP4F2 is the only known enzyme to ω-hydroxylate tocotrienols and tocopherols which are forms (vitamers) of vitamin E, thus making it a key regulator of circulating plasma vitamin E levels.<ref name="pmid15753130">{{cite journal | vauthors = Parker RS, Sontag TJ, Swanson JE, McCormick CC | title = Discovery, characterization, and significance of the cytochrome P450 omega-hydroxylase pathway of vitamin E catabolism | journal = Annals of the New York Academy of Sciences | volume = 1031 | pages = 13–21 | date = December 2004 | issue = 1 | pmid = 15753130 | doi = 10.1196/annals.1331.002 | bibcode = 2004NYASA1031...13P | s2cid = 33584273 }}</ref><ref name="pmid18433732" /><ref name="pmid20861217">{{cite journal | vauthors = Bardowell SA, Stec DE, Parker RS | title = Common variants of cytochrome P450 4F2 exhibit altered vitamin E-{omega}-hydroxylase specific activity | journal = The Journal of Nutrition | volume = 140 | issue = 11 | pages = 1901–1906 | date = November 2010 | pmid = 20861217 | pmc = 2955872 | doi = 10.3945/jn.110.128579 }}</ref> It catalyzes ω-hydroxylation of the phytyl chain of tocopherols, with preference for γ-tocopherols over α-tocopherols, thus promoting retention of α-tocopherols in tissues.<ref name="pmid11997390">{{cite journal | vauthors = Sontag TJ, Parker RS | title = Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status | journal = The Journal of Biological Chemistry | volume = 277 | issue = 28 | pages = 25290–25296 | date = July 2002 | pmid = 11997390 | doi = 10.1074/jbc.M201466200 | doi-access = free | s2cid = 743292 }}</ref>

Vitamin E is a collective term for eight different molecules that have antioxidant properties and protect cell membranes from oxidative damage. They are divided into two groups: tocotrienols and tocopherols. Both groups have a chromanol ring, which is the active part of the molecule, and a phytyl chain, which is a long hydrocarbon tail. CYP4F2 shortens the phytyl chain of both tocopherols and tocotrienols by ω-hydroxylation, which reduces their biological activity and stability.<ref name="pmid11997390" />

Vitamin K is a collective term for two natural forms of vitamin K: vitamin K<sub>1</sub> (phylloquinone) and vitamin K<sub>2</sub> (menaquinone).<ref name="omim" /><ref name="pmid23132553" /><ref name="pmid20335999">{{cite journal |vauthors=Kurosu M, Begari E |title=Vitamin K2 in electron transport system: are enzymes involved in vitamin K2 biosynthesis promising drug targets? |journal=Molecules |volume=15 |issue=3 |pages=1531–53 |date=March 2010 |pmid=20335999 |pmc=6257245 |doi=10.3390/molecules15031531 |doi-access=free}}</ref> Vitamin K is essential for the synthesis of several proteins involved in blood clotting and bone metabolism.<ref name="omim" /><ref name="pmid23132553" /> Vitamin K<sub>1</sub> has a phytyl chain, similar to vitamin E, while vitamin K<sub>2</sub> has an isoprenoid chain, which is a series of five-carbon units. CYP4F2 shortens the phytyl chain of vitamin K<sub>1</sub> and the isoprenoid chain of vitamin K<sub>2</sub> by ω-hydroxylation, which reduces their biological activity and stability.<ref name="pmid23132553" />

Both types of Vitamin K (K<sub>1</sub> and K<sub>2</sub>) can be used as co-factors for γ-glutamyl carboxylase, an enzyme that catalyzes the post-translational modification of Vitamin K-dependent proteins, thus biochemically activating the proteins involved in blood coagulation and bone mineralization.<ref>{{cite journal|doi=10.1182/blood.V93.6.1798.406k22_1798_1808 |title=Vitamin K-Dependent Biosynthesis of γ-Carboxyglutamic Acid |date=1999 |journal=Blood |volume=93 |issue=6 |pages=1798–1808 |pmid=10068650 | vauthors = Furie B, Bouchard BA, Furie BC }}</ref><ref name="pmid35628569">{{cite journal |vauthors=Berkner KL, Runge KW |title=Vitamin K-Dependent Protein Activation: Normal Gamma-Glutamyl Carboxylation and Disruption in Disease |journal=Int J Mol Sci |volume=23 |issue=10 |article-number=5759 |date=May 2022 |pmid=35628569 |pmc=9146348 |doi=10.3390/ijms23105759 |doi-access=free }}</ref>

CYP4F2 plays a pivotal role in modulating circulating levels of vitamin K<sub>1</sub> by ω-hydroxylating and deactivating it: in the liver, where this enzyme is predominantly expressed, it functions as a primary oxidase responsible for metabolizing vitamin K<sub>1</sub> into hydroxylated forms. By doing so, it acts synergistically with VKORC1 enzyme to prevent excessive accumulation of biologically active vitamin K in the body. Termed the "siphoning" pathway,<ref name="pmid37161313">{{cite journal | vauthors = Farajzadeh-Dehkordi M, Mafakher L, Samiee-Rad F, Rahmani B | title = Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact | journal = BMC Molecular and Cell Biology | volume = 24 | issue = 1 | article-number = 17 | date = May 2023 | pmid = 37161313 | pmc = 10170697 | doi = 10.1186/s12860-023-00479-0 | doi-access = free }}</ref> this mechanism primarily occurs when there is an excess amount of vitamin K<sub>1</sub> present. This enzymatic process positions CYP4F2 as a critical negative regulator for maintaining appropriate levels of active vitamin K<sub>1</sub> within the body.<ref name="pmid23132553">{{cite journal | vauthors = Danese E, Montagnana M, Johnson JA, Rettie AE, Zambon CF, Lubitz SA, Suarez-Kurtz G, Cavallari LH, Zhao L, Huang M, Nakamura Y, Mushiroda T, Kringen MK, Borgiani P, Ciccacci C, Au NT, Langaee T, Siguret V, Loriot MA, Sagreiya H, Altman RB, Shahin MH, Scott SA, Khalifa SI, Chowbay B, Suriapranata IM, Teichert M, Stricker BH, Taljaard M, Botton MR, Zhang JE, Pirmohamed M, Zhang X, Carlquist JF, Horne BD, Lee MT, Pengo V, Guidi GC, Minuz P, Fava C | title = Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis | journal = Clinical Pharmacology and Therapeutics | volume = 92 | issue = 6 | pages = 746–756 | date = December 2012 | pmid = 23132553 | pmc = 3731755 | doi = 10.1038/clpt.2012.184 }}</ref><ref name="pmid19297519">{{cite journal | vauthors = McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE | title = CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant | journal = Molecular Pharmacology | volume = 75 | issue = 6 | pages = 1337–1346 | date = June 2009 | pmid = 19297519 | pmc = 2684883 | doi = 10.1124/mol.109.054833 }}</ref>

=== Biosynthesis of 20-HETE === CYP4F2 along with CYP4A22, CYP4A11, CYP4F3 and CYP2U1 enzymes also metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) by an ω-oxidation reaction, with the predominant 20-HETE-synthesizing enzymes in humans being CYP4F2, followed by CYP4A11.<ref name="pmid22706230"/>

One of the main roles of 20-HETE is to regulate various physiological processes within the body, such as blood flow, vascularization (or angiogenesis, that is the growth of blood vessels), maintenance of proper blood pressure, and kidney tubule absorption of ions in rodents and possibly humans.<ref name="pmid25813407">{{cite journal | vauthors = Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC | title = Vascular actions of 20-HETE | journal = Prostaglandins & Other Lipid Mediators | volume = 120 | pages = 9–16 | date = July 2015 | pmid = 25813407 | pmc = 4575602 | doi = 10.1016/j.prostaglandins.2015.03.002 }}</ref> By controlling blood flow and vascularization, it helps with the formation of new blood vessels when needed. To influence blood pressure levels, it regulates the diameter of blood vessels and constriction or relaxation of smooth muscles that line them. To regulate ion transport and water reabsorption in kidney tubules, it regulates how ions are absorbed or excreted by kidney cells, ultimately impacting electrolyte balance within the bodies. Research on animal models suggests that changes in levels or activity of 20-HETE may be involved in conditions such as hypertension (high blood pressure), renal diseases (kidney disorders), cerebral ischemia (reduced blood flow to the brain), and even cancer progression.<ref name="pmid35659370">{{cite book |vauthors=Froogh G, Garcia V, Laniado Schwartzman M |title=New Targets for the Treatment of Hypertension and Associated Diseases |chapter=The CYP/20-HETE/GPR75 axis in hypertension |series=Adv Pharmacol |volume=94 |pages=1–25 |date=2022 |publisher=Academic Press |pmid=35659370 |pmc=10123763 |doi=10.1016/bs.apha.2022.02.003 |isbn=978-0-323-91087-3 }}</ref><ref name="pmid34374423">{{cite journal | vauthors = Gonzalez-Fernandez E, Liu Y, Auchus AP, Fan F, Roman RJ | title = Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE | journal = Clinical Science | volume = 135 | issue = 15 | pages = 1929–1944 | date = August 2021 | pmid = 34374423 | pmc = 8783562 | doi = 10.1042/CS20201033 }}</ref><ref name="pmid31514409"/>

The production and actions of 20-HETE can be influenced by genetic variations known in the ''CYP4F2'' gene. These variations may alter how efficiently arachidonic acid is converted into 20-HETE, affecting its overall impact on bodily functions.<ref name="pmid30296490">{{cite journal | vauthors = Fava C, Bonafini S | title = Eicosanoids via CYP450 and cardiovascular disease: Hints from genetic and nutrition studies | journal = Prostaglandins & Other Lipid Mediators | volume = 139 | issue = | pages = 41–47 | date = November 2018 | pmid = 30296490 | doi = 10.1016/j.prostaglandins.2018.10.001 | s2cid = 52943912 }}</ref>

=== Drug metabolism === Drug metabolism involves the breakdown and transformation of drugs into their active or inactive forms. The CYP4F2 enzyme plays a significant role in regulating the bioactivation of certain drugs.<ref name="pmid33346393"/>

Specifically, the enzyme regulates the bioactivation of the anti-parasitic drug pafuramidine, a prodrug that requires enzymatic conversion to its bioactive form furamidine. Several studies have identified CYP4F2 as one of the key enzymes responsible for this conversion in human liver microsomes and enteric microsomes.<ref name="pmid17709372">{{cite journal | vauthors = Wang MZ, Wu JQ, Bridges AS, Zeldin DC, Kornbluth S, Tidwell RR, Hall JE, Paine MF | title = Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine | journal = Drug Metabolism and Disposition | volume = 35 | issue = 11 | pages = 2067–2075 | date = November 2007 | pmid = 17709372 | pmc = 2364724 | doi = 10.1124/dmd.107.016428 }}</ref><ref name="pmid16997912">{{cite journal | vauthors = Wang MZ, Saulter JY, Usuki E, Cheung YL, Hall M, Bridges AS, Loewen G, Parkinson OT, Stephens CE, Allen JL, Zeldin DC, Boykin DW, Tidwell RR, Parkinson A, Paine MF, Hall JE | title = CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] | journal = Drug Metabolism and Disposition | volume = 34 | issue = 12 | pages = 1985–1994 | date = December 2006 | pmid = 16997912 | pmc = 2077835 | doi = 10.1124/dmd.106.010587 }}</ref> CYP4F2 is also involved in the metabolism of fingolimod, a drug used to treat multiple sclerosis.<ref name="pmid22149256">{{cite journal |vauthors=David OJ, Kovarik JM, Schmouder RL |title=Clinical pharmacokinetics of fingolimod |journal=Clin Pharmacokinet |volume=51 |issue=1 |pages=15–28 |date=January 2012 |pmid=22149256 |doi=10.2165/11596550-000000000-00000 |s2cid=207301139 }}</ref>

== Clinical significance == ===Genetic variants=== Genetic variations in ''CYP4F2'' play a role in physiological processes and health outcomes.<ref name="pmid33080066"/> Genetic variations in ''CYP4F2'' are considered in personalized treatments related to drug dosages and vitamin supplementation strategies.<ref name="pmid35247148">{{cite journal | vauthors = Fahmi AM, Elewa H, El Jilany I | title = Warfarin dosing strategies evolution and its progress in the era of precision medicine, a narrative review | journal = International Journal of Clinical Pharmacy | volume = 44 | issue = 3 | pages = 599–607 | date = June 2022 | pmid = 35247148 | pmc = 9200678 | doi = 10.1007/s11096-022-01386-8 }}</ref>

Confirmed variations in ''CYP4F2'' serve as biomarkers for individual differences in response to warfarin—adjusting warfarin dosage based on genetic information has demonstrated a decrease in negative clinical outcomes.<ref name="pmid38443337">{{cite journal |vauthors=Cross B, Turner RM, Zhang JE, Pirmohamed M |title=Being precise with anticoagulation to reduce adverse drug reactions: are we there yet? |journal=Pharmacogenomics J |volume=24 |issue=2 |article-number=7 |date=March 2024 |pmid=38443337 |pmc=10914631 |doi=10.1038/s41397-024-00329-y}}</ref>

Warfarin dosing algorithms that specifically incorporate the ''CYP4F2'' genetic variants are a subset of the broader range of warfarin dosing algorithms. As of May 2020, 92 out of 433 described warfarin dosing algorithms in the literature included ''CYP4F2'' variants; the other covariates included in these algorithms have been age, concomitant medications, weight, and the variants in the other genes: ''CYP2C9'' and ''VKORC1''.<ref name="pmid38443337"/>

One specific genetic variant which produces the enzyme with valine residue replaced to methionine residue at position 433 of the protein (V433M substitution), a single-nucleotide polymorphism denoted as CYP4F2*3<ref name="pharmgkbPA165860687">{{cite web | url=https://www.pharmgkb.org/haplotype/PA165860687 | title=Haplotype CYP4F2*3 | website=PharmGKB | publisher=Stanford University | access-date=26 November 2023 | archive-date=26 November 2023 | archive-url=https://web.archive.org/web/20231126080001/https://www.pharmgkb.org/haplotype/PA165860687 | url-status=live }}</ref> (rs2108622),<ref name="rs2108622">{{NCBI RefSNP|url=https://www.ncbi.nlm.nih.gov/snp/rs2108622 | title=Rs2108622 RefSNP Report - DBSNP - NCBI }}</ref> that is present in 28% of global population,<ref name="rs2108622-frequency">{{NCBI RefSNP|url=https://www.ncbi.nlm.nih.gov/snp/rs2108622#frequency_tab | title=Rs2108622 RefSNP Report - DBSNP - NCBI - Allele frequency}}</ref> leads to reduced enzymatic activity due to decrease in steady-state hepatic concentrations of the enzyme.<ref name="pmid30506689" /><ref name="pmid26981194" /> This variant has a role in eicosanoid and Vitamin E metabolism,<ref name="pmid20861217" /><ref name="pmid21729881">{{cite journal | vauthors = Major JM, Yu K, Wheeler W, Zhang H, Cornelis MC, Wright ME, Yeager M, Snyder K, Weinstein SJ, Mondul A, Eliassen H, Purdue M, Hazra A, McCarty CA, Hendrickson S, Virtamo J, Hunter D, Chanock S, Kraft P, Albanes D | title = Genome-wide association study identifies common variants associated with circulating vitamin E levels | journal = Human Molecular Genetics | volume = 20 | issue = 19 | pages = 3876–3883 | date = October 2011 | pmid = 21729881 | pmc = 3168288 | doi = 10.1093/hmg/ddr296 }}</ref><ref name="pmid26981194" /> in the bioavailability of Vitamin K,<ref name="pmid23132553" /> in affecting doses of anticoagulants such as warfarin<ref name="pmid33080066"/><ref name="pmid28620303" /> or coumarin,<ref name="pmid30506689" /> and is also associated with hypertension,<ref name="pmid30932691">{{cite journal | vauthors = Geng H, Li B, Wang Y, Wang L | title = Association Between the ''CYP4F2'' Gene rs1558139 and rs2108622 Polymorphisms and Hypertension: A Meta-Analysis | journal = Genetic Testing and Molecular Biomarkers | volume = 23 | issue = 5 | pages = 342–347 | date = May 2019 | pmid = 30932691 | doi = 10.1089/gtmb.2018.0202 | s2cid = 89620562 }}</ref><ref name="pmid26634476">{{cite journal | vauthors = Luo XH, Li GR, Li HY | title = Association of the CYP4F2 rs2108622 genetic polymorphism with hypertension: a meta-analysis | journal = Genetics and Molecular Research | volume = 14 | issue = 4 | pages = 15133–15139 | date = November 2015 | pmid = 26634476 | doi = 10.4238/2015.November.25.1 | doi-broken-date = 27 July 2025 | doi-access = free }}</ref> with increased risk of cerebral infarction (i.e. ischemic stroke) and myocardial infarction.<ref name="pmid31514409">{{cite journal | vauthors = Shekhar S, Varghese K, Li M, Fan L, Booz GW, Roman RJ, Fan F | title = Conflicting Roles of 20-HETE in Hypertension and Stroke | journal = International Journal of Molecular Sciences | volume = 20 | issue = 18 | page = 4500 | date = September 2019 | pmid = 31514409 | pmc = 6770042 | doi = 10.3390/ijms20184500 | doi-access = free }}</ref> Individuals who carry this genetic variant, either in heterozygous form (on one chromosome) or homozygous form (on both chromosomes), may have an increased risk of excessive anticoagulation when treated with warfarin, although not all studies confirm this association.<ref name="pharmgkb1449269278">{{cite web | url=https://www.pharmgkb.org/clinicalAnnotation/1449269278 | title=Clinical Annotation for rs2108622 and warfarin | website=PharmGKB | publisher=Stanford University | access-date=26 November 2023 | archive-date=26 November 2023 | archive-url=https://web.archive.org/web/20231126075958/https://www.pharmgkb.org/clinicalAnnotation/1449269278 | url-status=live }}</ref> This variant accounted for a difference in warfarin dose of approximately 1&nbsp;mg/day between CC and TT subjects.<ref name="pmid38443337"/> Most of the studies on warfarin pharmacogenetics, including those involving CYP4F2, have been conducted in European ancestry patients; still, there has been significant activity in developing dosing algorithms for individuals of Asian ancestry.<ref name="pmid38443337"/>

The CYP4F2 enzyme also regulates the bioactivation of anti-parasitic drug pafuramidine; as such, genetic variations in the ''CYP4F2'' that alter enzyme function can impact the efficacy and safety of these drugs for patients receiving therapy. For example, individuals with a variation that leads to reduced activity of the enzyme may not fully metabolize pafuramidine, leading to lower drug concentrations and reducing its effectiveness against malaria. In contrast, variations associated with increased enzyme activity could result in faster metabolism of pafuramidine and furamidine, leading to higher than expected drug concentrations which may increase the risk of adverse effects.<ref name="pmid25370453"/>

=== Drug interactions === There can be interactions between the drugs that rely on CYP4F2 on their metabolism or bioactivation (e.g., fingolimod, furamidine, warfarin)<ref name="pmid22149256"/><ref name="pmid24816681">{{cite journal |vauthors=Michaels S, Wang MZ |title=The revised human liver cytochrome P450 "Pie": absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics |journal=Drug Metab Dispos |volume=42 |issue=8 |pages=1241–51 |date=August 2014 |pmid=24816681 |pmc=4109210 |doi=10.1124/dmd.114.058040 }}</ref> and the substances that inhibit or induce ''CYP4F2'' expression, such as statins and peroxisome proliferators, 25-hydroxycholesterol, vitamin K, ketoconazole, sesamin, and others.<ref name="pmid25370453"/> For example, ketoconazole inhibits CYP4F2 and has been observed to increase the plasma concentrations of fingolimod.<ref name="pmid22149256"/>

===Biological target=== CYP4F2, along with the other enzymes that convert arachidonic acid to 20-HETE, can be a drug target in disease-modifying therapy for cancer. 20-HETE is a molecule that affects tumor progression, angiogenesis, and blood pressure regulation in the circulatory system and kidneys.<ref name="omim" /><ref name="pmid33112969"/> In the tumor microenvironment, proinflammatory cytokines can induce or inhibit CYP4F2 and other enzymes, which can promote carcinogenesis and affect chemotherapy, leading to adverse effects, toxicity, or therapeutic failure.<ref name="pmid34178680">{{cite journal |vauthors=Gómez-Valenzuela F, Escobar E, Pérez-Tomás R, Montecinos VP |title=The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition |journal=Front Oncol |volume=11 |article-number=686792 |date=2021 |pmid=34178680 |pmc=8222670 |doi=10.3389/fonc.2021.686792 |doi-access=free}}</ref><ref name="pmid24901008">{{cite journal |vauthors=Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA |title=Chronic inflammation and cytokines in the tumor microenvironment |journal=J Immunol Res |volume=2014 |article-number=149185 |date=2014 |pmid=24901008 |pmc=4036716 |doi=10.1155/2014/149185 |doi-access=free}}</ref> CYP enzymes could be targeted to modify the course of diseases like cancer.<ref name="pmid20233842">{{cite journal |vauthors=Swanson HI, Njar VC, Yu Z, Castro DJ, Gonzalez FJ, Williams DE, Huang Y, Kong AN, Doloff JC, Ma J, Waxman DJ, Scott EE |title=Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy |journal=Drug Metab Dispos |volume=38 |issue=4 |pages=539–44 |date=April 2010 |pmid=20233842 |pmc=2845935 |doi=10.1124/dmd.109.031351 }}</ref> Targeting CYPs in preclinical and clinical trials for chemoprevention and chemotherapy has become an effective way to improve antitumor treatment outcomes.<ref name="pmid31309254">{{cite journal |vauthors=van Eijk M, Boosman RJ, Schinkel AH, Huitema AD, Beijnen JH |title=Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes |journal=Cancer Chemother Pharmacol |volume=84 |issue=3 |pages=487–499 |date=September 2019 |pmid=31309254 |pmc=6682574 |doi=10.1007/s00280-019-03905-3 }}</ref> Intratumoral CYP enzymes can play a role in the fate of antitumor agents by drug activation or inactivation.<ref name="pmid34930302">{{cite journal |vauthors=Dai E, Zhu Z, Wahed S, Qu Z, Storkus WJ, Guo ZS |title=Epigenetic modulation of antitumor immunity for improved cancer immunotherapy |journal=Mol Cancer |volume=20 |issue=1 |article-number=171 |date=December 2021 |pmid=34930302 |pmc=8691037 |doi=10.1186/s12943-021-01464-x |doi-access=free}}</ref> Still, they can also provide a mechanism for drug resistance due to their aberrant expression and their supporting roles in tumor progression and metastasis.<ref name="pmid33723723">{{cite journal |vauthors=Song Y, Li C, Liu G, Liu R, Chen Y, Li W, Cao Z, Zhao B, Lu C, Liu Y |title=Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes |journal=Clin Pharmacokinet |volume=60 |issue=5 |pages=585–601 |date=May 2021 |pmid=33723723 |doi=10.1007/s40262-021-01001-5 |s2cid=232237738 }}</ref><ref name="omim" />

== History == The ''CYP4F2'' gene was mapped to chromosome 19 in 1997 through analysis of monochromosomal human-rodent cell hybrids.<ref name="pmid9271096">{{cite journal | vauthors = Heng YM, Kuo CS, Jones PS, Savory R, Schulz RM, Tomlinson SR, Gray TJ, Bell DR | title = A novel murine P-450 gene, Cyp4a14, is part of a cluster of Cyp4a and Cyp4b, but not of CYP4F, genes in mouse and humans | journal = The Biochemical Journal | volume = 325 | issue = Pt 3 | pages = 741–749 | date = August 1997 | pmid = 9271096 | pmc = 1218619 | doi = 10.1042/bj3250741 }}</ref> The gene was subsequently isolated and its genomic organization characterized, revealing at least 13 exons with a structure similar to ''CYP4F3''. The CYP4F2 protein was shown to be constitutively expressed in the HepG2 hepatoma cell line and to play a role in inactivating leukotriene B<sub>4</sub>.<ref name="pmid10492403">{{cite journal | vauthors = Kikuta Y, Miyauchi Y, Kusunose E, Kusunose M | title = Expression and molecular cloning of human liver leukotriene B4 omega-hydroxylase (CYP4F2) gene | journal = DNA and Cell Biology | volume = 18 | issue = 9 | pages = 723–730 | date = September 1999 | pmid = 10492403 | doi = 10.1089/104454999315006 }}</ref><ref name="omim">{{OMIM|604426}}</ref>

A key functional polymorphism, the V433M substitution (CYP4F2*3, rs2108622), was identified in 2007 with a minor allele frequency of 9-21% in African and European American populations. ''In vitro'' assays showed this variant decreased 20-HETE production to 56-66% of normal levels while leaving LTB4 omega-hydroxylation unaffected.<ref name="pmid17341693"/><ref name="omim" /><ref name="pmid34594219"/> The following year, this variant was linked to altered warfarin dose requirements,<ref name="pmid18250228">{{cite journal | vauthors = Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, Hubbard J, Turpaz Y, Langaee TY, Eby C, King CR, Brower A, Schmelzer JR, Glurich I, Vidaillet HJ, Yale SH, Qi Zhang K, Berg RL, Burmester JK | title = CYP4F2 genetic variant alters required warfarin dose | journal = Blood | volume = 111 | issue = 8 | pages = 4106–4112 | date = April 2008 | pmid = 18250228 | pmc = 2288721 | doi = 10.1182/blood-2007-11-122010 }}</ref> and subsequent genotyping of 963 individuals across 7 geographic regions confirmed its relevance to warfarin dosing algorithms worldwide.<ref name="omim"/> More recently, computational analysis using 14 bioinformatics tools has demonstrated that the V433M substitution reduces protein compactness and stability, altering the overall structural conformation and flexibility of the CYP4F2 enzyme.<ref name="pmid37161313"/>

== References == <references /> {{Authority control}} {{Leukotriene signaling modulators}} {{Cytochrome P450}}

Category:Cytochrome P450