CYP4F2

CYP4F2
Identifiers
AliasesCYP4F2, CPF2, cytochrome P450 family 4 subfamily F member 2
External IDsOMIM: 604426 MGI: 1919304 HomoloGene: 128623 GeneCards: CYP4F2
Orthologs
SpeciesHumanMouse
Entrez

8529

72054

Ensembl

ENSG00000186115

ENSMUSG00000003484

UniProt

P78329

Q99N16

RefSeq (mRNA)

NM_001082

NM_024444

RefSeq (protein)

NP_001073

NP_077764

Location (UCSC)Chr 19: 15.88 – 15.9 MbChr 8: 71.99 – 72.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Leukotriene-B(4) omega-hydroxylase 1 is an enzyme protein involved in the metabolism of various endogenous substrates (mainly the fatty acids) and xenobiotics (including pharmaceutical drugs). The most notable substrate of the enzyme is leukotriene B4, a potent mediator of inflammation. The CYP4F2 gene encodes the enzyme in humans.

Function

The Leukotriene-B(4) omega-hydroxylase 1, or simply the CYP4F2 enzyme protein, encoded by CYP4F2 gene in humans,[5][6][7] is a member of the cytochrome P450 superfamily of enzymes. The CYP4F2 gene belongs to a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F11, is approximately 16 kb away.[7]

The enzyme is called Leukotriene-B(4) omega-hydroxylase 1 because it starts the process of inactivating and degrading leukotriene B4, a potent mediator of inflammation.

The cytochrome P450 enzymes are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, fatty acids, and other lipids.

The CYP4F2 enzyme protein presents in endoplasmic reticulum.

The enzyme CYP4F2 is involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins.[8] It controls the bioavailability of Vitamin E. It also controls the bioavailability of Vitamin K, a co-factor required for blood to clot. Variations in the CYP4F2 gene that affect the bioavailability of Vitamin K also affect the dosing of Vitamin K antagonists such as warfarin, coumarin or acenocoumarol.[9][10] The enzyme also regulates the bioactivation of various drugs, e.g., the anti-malarial drug pafuramidine and the anti-parasitic drug furamidine. It also plays a role in renal water homeostasis.[11]

Inactivation of Leukotriene B4

Arachidonic acid is a precursor of the eicosanoid molecules that control immune response and inflammation. Acute inflammation on injury or infection protects the body from pathogens. It should also be taken into consideration that if inflammation is continuing for a notably long time, healthy cells and tissues are damaged. Thus, the inflammation must be carefully controlled. Leukotriene B4 is a pro-inflammatory eicosanoid with strong chemoattractant properties. It can be rapidly produced by activated innate immune cells, such as neutrophils, macrophages and mast cells.[12] It induces the activation of polymorphonuclear leukocytes, monocytes and fibroblasts, the production of superoxide and the release of cytokines to attract neutrophils.[13][14][15][16] CYP4F2 starts the process of inactivating and degrading leukotriene B4, by converting it to its ω-hydroxylated metabolite 20-hydroxyleukotriene B4 in human liver microsomes.[17] CYP4F2 then coverts 20-hydroxyleukotriene B4 to 20-oxoleukotriene B4 and then to 20-carboxyleukotrene B4.[18]

Chain shortening

It is α-, β-, and ω-oxidation of fatty acid carbon chains that degrades the acids, with the preferred pathway being the β-oxidation in the mitochondria and peroxisomes. Very long chain fatty acids 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.[19]

Metabolism of vitamins

The enzyme plays an important role in vitamin metabolism by chain shortening.[20][21][22][23]

CYP4F2 is the only known enzyme to ω-hydroxylate tocotrienols and tocopherols (types of Vitamin E), thus making it a key regulator of circulating plasma Vitamin E levels.[24][16][25] It catalyzes ω-hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over α-tocopherols, thus promoting retention of α-tocopherols in tissues.[26]

Both types of Vitamin K (K1 and K2) can be used as co-factors for γ-glutamyl carboxylase, an enzyme that catalyzes the posttranslational modification of Vitamin K-dependent proteins, thus biochemically activating the proteins involved in blood coagulation and bone mineralization. CYP4F2 ω-xydroxylates and inactivates Vitamin K. As a result, CYP4F2 becomes vital negative regulator of circulating Vitamin K levels.[27][28]

Production of 20-HETE

CYP4F2 along with CYP4A22, CYP4A11, CYP4F3 and CYP2U1 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. 20-HETE regulates blood flow, vascularization, blood pressure, and kidney tubule absorption of ions in rodents and possibly humans.[29] The CYP4F2*3 (rs2108622) polymorphism (the enzyme protein with valine residue replaced to methionine residue at position 433) leads to reduced capacity to metabolize arachidonic acid to 20-HETE, but increased urinary excretion of 20-HETE.[15][30] Researchers have identified at least 3 more single-nucleotide polymorphisms (2024C>G P85A; 80C>T A27V rs771576634; 139C>T R47C rs115517770) which may affect conversion of arachidonic acid to HETE-20.[31]

Metabolism of fatty acids

Members of the CYP4A and CYP4F sub-families may also ω-hydroxylate and thereby reduce the activity of various fatty acid metabolites of arachidonic acid including leukotriene B4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins that are involved in regulating various inflammatory, vascular, and other responses in animals and humans.[18][16] This hydroxylation-induced inactivation may underlie the proposed roles of the cytochromes in dampening inflammatory responses and the reported associations of certain CYP4F2 single-nucleotide polymorphisms (SNPs) with human Crohn's disease[32][33] and Coeliac disease.[16][34][35]

Tye enzyme catalyzes ω-hydroxylation of 3-hydroxy fatty acids.[36] It converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to ω-hydroxylated metabolites.[37] It also contributes to the degradation of very long-chain fatty acids by catalyzing successive ω-oxidations and chain shortening.[38][39]

Anti-parasitic drugs

Pafuramidine is a prodrug of furamidine, an antiparasitic drug. There are at least two studies which determined that CYP4F2 is one of the enzymes responsible for the conversion of pafuramidine to furamidine in human liver microsomes and human enteric microsomes.[19][40][41]

Genetic variants

The T allele at rs2108622, which has been designated as CYP4F2*3 in the Human CYP Allele Nomenclature Database by the Pharmacogene Variation Consortium, produces the enzyme with valine residue replaced to methionine residue at position 433, a single-nucleotide polymorphism, resulting in reduced CYP4F2 enzyme activity for some substances,[42] due to decrease in steady-state hepatic concentrations of the enzyme.[27] This polymorphism, CYP4F2*3 (1347C>T; NM_001082.5:c.1297G>A; p. Val433Met; rs2108622), is the most studied and most pharmacogenetically relevant. Another polymorphism, CYP4F2*2 (NM_001082.4:c.34T>G; p.Trp12Gly; rs3093105), increases specific enzyme activity for some substances.

Studies have shown that CYP4F2*3 polymorphism has a role in eicosanoid and Vitamin E metabolism,[25][43] in the bioavailability of Vitamin K, in affecting doses of warfarin[44][45] or coumarin,[10] and is also associated with hypertension,[30][46][47][48] with increased risk of cerebral infarction (i.e. ischemic stroke)[49][50][51] and myocardial infarction.[52][53]

Research

The molecular mediators, inducers, and inhibitors that regulate CYP4F2 expression have mostly been elucidated in in vitro systems:[9]

With the exception of ketoconazole and sesamin, these findings have not been confirmed in clinical studies.[9][60] The inhibitory effect of ketoconazole has been confirmed by a study of 21 participants with different CYP4F2*3 variants enrolled (8 for *1/*1, 7 for *1/*3, and 6 for *3/*3).[57] The inhibitory effect of sesamin has been confirmed by a randomized, controlled crossover trial, where 33 overweight men and women consumed 25 grams per day of sesame (approximately 50 mg/d of sesame lignan) for 5 weeks, resulting in a 28% decrease in plasma and a 32% decrease in urinary 20-HETE, while urinary sodium, potassium, and blood pressure were not affected.[61]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000186115 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000003484 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Chen L, Hardwick JP (January 1993). "Identification of a new P450 subfamily, CYP4F1, expressed in rat hepatic tumors". Archives of Biochemistry and Biophysics. 300 (1): 18–23. doi:10.1006/abbi.1993.1003. PMID 8424651.
  6. ↑ Kikuta Y, Kusunose E, Kondo T, Yamamoto S, Kinoshita H, Kusunose M (July 1994). "Cloning and expression of a novel form of leukotriene B4 omega-hydroxylase from human liver". FEBS Letters. 348 (1): 70–4. doi:10.1016/0014-5793(94)00587-7. PMID 8026587. S2CID 83948293.
  7. 1 2 "CYP4F2 cytochrome P450 family 4 subfamily F member 2". National Center for Biotechnology Information. Archived from the original on 10 April 2021. Retrieved 30 November 2020. This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum. The enzyme starts the process of inactivating and degrading leukotriene B4, a potent mediator of inflammation. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F11, is approximately 16 kb away.Public Domain This article incorporates text from this source, which is in the public domain.
  8. ↑ "CYP4F2 Gene". Archived from the original on 6 August 2020. Retrieved 3 July 2020.
  9. 1 2 3 "Very Important Pharmacogene: CYP4F2". PharmGKB. Stanford University. Archived from the original on 5 July 2020. Retrieved 3 July 2020.
  10. 1 2 Danese E, Raimondi S, Montagnana M, Tagetti A, Langaee T, Borgiani P, et al. (June 2019). "Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals". Clinical Pharmacology and Therapeutics. 105 (6): 1477–1491. doi:10.1002/cpt.1323. PMC 6542461. PMID 30506689.
  11. ↑ Lasker JM, Chen WB, Wolf I, Bloswick BP, Wilson PD, Powell PK (February 2000). "Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11". The Journal of Biological Chemistry. 275 (6): 4118–26. doi:10.1074/jbc.275.6.4118. PMID 10660572. S2CID 41956184.
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  13. ↑ Yokomizo T, Izumi T, Shimizu T (January 2001). "Leukotriene B4: metabolism and signal transduction". Archives of Biochemistry and Biophysics. 385 (2): 231–41. doi:10.1006/abbi.2000.2168. PMID 11368003.
  14. ↑ Kalsotra A, Strobel HW (December 2006). "Cytochrome P450 4F subfamily: at the crossroads of eicosanoid and drug metabolism". Pharmacology & Therapeutics. 112 (3): 589–611. doi:10.1016/j.pharmthera.2006.03.008. PMID 16926051.
  15. 1 2 Stec DE, Roman RJ, Flasch A, Rieder MJ (June 2007). "Functional polymorphism in human CYP4F2 decreases 20-HETE production". Physiological Genomics. 30 (1): 74–81. doi:10.1152/physiolgenomics.00003.2007. PMID 17341693.
  16. 1 2 3 4 Hardwick JP (June 2008). "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases". Biochemical Pharmacology. 75 (12): 2263–75. doi:10.1016/j.bcp.2008.03.004. PMID 18433732.
  17. ↑ Jin R, Koop DR, Raucy JL, Lasker JM (November 1998). "Role of human CYP4F2 in hepatic catabolism of the proinflammatory agent leukotriene B4". Archives of Biochemistry and Biophysics. 359 (1): 89–98. doi:10.1006/abbi.1998.0880. PMID 9799565.
  18. 1 2 Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, et al. (July 1998). "Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3)". Archives of Biochemistry and Biophysics. 355 (2): 201–5. doi:10.1006/abbi.1998.0724. PMID 9675028.
  19. 1 2 Alvarellos ML, Sangkuhl K, Daneshjou R, Whirl-Carrillo M, Altman RB, Klein TE (January 2015). "PharmGKB summary: very important pharmacogene information for CYP4F2". Pharmacogenetics and Genomics. 25 (1): 41–7. doi:10.1097/FPC.0000000000000100. PMC 4261059. PMID 25370453.
  20. ↑ Martha H. Stipanuk, Marie A. Caudill (2018). Biochemical, Physiological, and Molecular Aspects of Human Nutrition - E-Book (4 ed.). Elsevier Health Sciences. p. 711. ISBN 9780323402132. Archived from the original on 15 July 2020. Retrieved 4 July 2020.{{cite book}}: CS1 maint: uses authors parameter (link)
  21. ↑ Volker Böhm (2018). Vitamin E. p. 60. ISBN 978-3-03842-906-7. Archived from the original on 5 July 2020. Retrieved 4 July 2020.
  22. ↑ Fred Snyder (6 December 2012). Lipid metabolism in mammals. Springer Science & Business Media. p. 44. ISBN 978-1-4684-2832-2. Archived from the original on 8 August 2020. Retrieved 12 July 2020.
  23. ↑ S. Numa, ed. (January 1984). Fatty Acid Metabolism and its Regulation. Elsevier. p. 132. ISBN 0444805281. Archived from the original on 7 July 2021. Retrieved 12 July 2020.
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  25. 1 2 Bardowell SA, Stec DE, Parker RS (November 2010). "Common variants of cytochrome P450 4F2 exhibit altered vitamin E-{omega}-hydroxylase specific activity". The Journal of Nutrition. 140 (11): 1901–6. doi:10.3945/jn.110.128579. PMC 2955872. PMID 20861217.
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  27. 1 2 Danese E, Montagnana M, Johnson JA, Rettie AE, Zambon CF, Lubitz SA, et al. (December 2012). "Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis". Clinical Pharmacology and Therapeutics. 92 (6): 746–56. doi:10.1038/clpt.2012.184. PMC 3731755. PMID 23132553.
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  30. 1 2 Ward NC, Croft KD, Puddey IB, Phillips M, van Bockxmeer F, Beilin LJ, Barden AE (July 2014). "The effect of a single nucleotide polymorphism of the CYP4F2 gene on blood pressure and 20-hydroxyeicosatetraenoic acid excretion after weight loss" (PDF). Journal of Hypertension. 32 (7): 1495–502, discussion 1502. doi:10.1097/HJH.0000000000000208. PMID 24984178. S2CID 6754178. Archived (PDF) from the original on 1 October 2019. Retrieved 1 October 2019.
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  55. ↑ Zhang X, Chen L, Hardwick JP (June 2000). "Promoter activity and regulation of the CYP4F2 leukotriene B(4) omega-hydroxylase gene by peroxisomal proliferators and retinoic acid in HepG2 cells". Archives of Biochemistry and Biophysics. 378 (2): 364–76. doi:10.1006/abbi.2000.1836. PMID 10860554.
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  57. 1 2 Park JW, Kim KA, Park JY (November 2019). "Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F2*3 Genetic Polymorphism on Pharmacokinetics of Vitamin K1". Journal of Clinical Pharmacology. 59 (11): 1453–1461. doi:10.1002/jcph.1444. PMID 31134657. S2CID 167218512.
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  59. 1 2 Tippin T, Chladek J, Keilholz L, Usuki E, Ogilvie B, Van Sickle K, Mommeja-Marin H, Grossi IM, Trost L (January 2014). "CYP4F2 is The Major Cytochrome P450 Enzyme Involved in CMX001 Metabolism". Drug Metabolism Reviews. 45: 84–85. Archived from the original on 7 July 2021. Retrieved 3 July 2020.
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  61. ↑ Wu JH, Hodgson JM, Clarke MW, Indrawan AP, Barden AE, Puddey IB, Croft KD (November 2009). "Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: in vitro and human studies". Hypertension. 54 (5): 1151–8. doi:10.1161/HYPERTENSIONAHA.109.139352. PMID 19786646. S2CID 207687898.
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