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The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, fatty acids, 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.<ref name="entrez"/>
The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, fatty acids, 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.<ref name="entrez"/>


The enzyme CYP4F2 regulates the bioavailability of [[Vitamin E]] and [[Vitamin K]], a co-factor that is critical to blood clotting. 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]].<ref name="PharmKGB">{{cite web |url=https://www.pharmgkb.org/vip/PA166169424 |title=Very Important Pharmacogene: CYP4F2}}</ref><ref name="coumarin">{{cite web |url=https://pubmed.ncbi.nlm.nih.gov/30506689/}}</ref> The enzyme also regulates bioactivation of various drugs, e.g. the anti-malarial drug pafuramidine.
The enzyme CYP4F2 regulates the bioavailability of [[Vitamin E]] and [[Vitamin K]], a co-factor that is critical to blood clotting. 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]].<ref name="PharmKGB">{{cite web |url=https://www.pharmgkb.org/vip/PA166169424 |title=Very Important Pharmacogene: CYP4F2}}</ref><ref name="coumarin">{{cite journal |pmid = 30506689|year = 2019|last1 = Danese|first1 = E.|last2 = Raimondi|first2 = S.|last3 = Montagnana|first3 = M.|last4 = Tagetti|first4 = A.|last5 = Langaee|first5 = T.|last6 = Borgiani|first6 = P.|last7 = Ciccacci|first7 = C.|last8 = Carcas|first8 = A. J.|last9 = Borobia|first9 = A. M.|last10 = Tong|first10 = H. Y.|last11 = Dávila-Fajardo|first11 = C.|last12 = Rodrigues Botton|first12 = M.|last13 = Bourgeois|first13 = S.|last14 = Deloukas|first14 = P.|last15 = Caldwell|first15 = M. D.|last16 = Burmester|first16 = J. K.|last17 = Berg|first17 = R. L.|last18 = Cavallari|first18 = L. H.|last19 = Drozda|first19 = K.|last20 = Huang|first20 = M.|last21 = Zhao|first21 = L. Z.|last22 = Cen|first22 = H. J.|last23 = Gonzalez-Conejero|first23 = R.|last24 = Roldan|first24 = V.|last25 = Nakamura|first25 = Y.|last26 = Mushiroda|first26 = T.|last27 = Gong|first27 = I. Y.|last28 = Kim|first28 = R. B.|last29 = Hirai|first29 = K.|last30 = Itoh|first30 = K.|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|doi = 10.1002/cpt.1323|pmc = 6542461|displayauthors = 29}}</ref> The enzyme also regulates bioactivation of various drugs, e.g. the anti-malarial drug pafuramidine.


=== Eicosanoids ===
=== Eicosanoids ===

Revision as of 20:26, 3 July 2020

CYP4F2
Identifiers
AliasesCYP4F2, CPF2, cytochrome P450 family 4 subfamily F member 2
External IDsOMIM: 604426; MGI: 1919304; HomoloGene: 128623; GeneCards: CYP4F2; OMA:CYP4F2 - orthologs
EC number1.14.14.94
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: 72.74 – 72.76 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Leukotriene-B(4) omega-hydroxylase 1 is an enzyme that in humans is encoded by the CYP4F2 gene.[5][6][7]

Function

Introduction

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, fatty acids, 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.[7]

The enzyme CYP4F2 regulates the bioavailability of Vitamin E and Vitamin K, a co-factor that is critical to blood clotting. 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.[8][9] The enzyme also regulates bioactivation of various drugs, e.g. the anti-malarial drug pafuramidine.

Eicosanoids

Arachidonic Acid is a precursor of the eicosanoids, which are signaling molecules that mediate the inflammation and immune response. Acute inflammation at the site of injury or infection protects the body from pathogens but prolonged inflammation damages healthy cells and tissue; thus inflammation must be tightly controlled. Leukotriene B 4 is a pro-inflammatory eicosanoid that induces activation of polymorphonuclear leukocytes, monocytes, and fibroblasts, generation of superoxide, and the release of cytokines to attract neutrophils.[10][11][12][13][14]

Metabolism of Arachidonic Acid to 20-Hydroxyeicosatetraenoic acid

CYP4F2 along with CYP4A22, CYP4A11, and 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.[15] Gene polymorphism variants of CYP4F2 are associated with the development of hypertension, cerebral infarction (i.e. ischemic stroke), and myocardial infarction.[16][17][18][18][19][17][18][20][20][21][22][23][24] The G1347A variant of CYP4F2 produces an enzyme with methionine in place of valium at position 433 (Val433Met; single nucleotide variant rs2108622); the variant enzyme has reduce capacity to metabolize arachidonic acid to 20-HETE but increased urinary excretion of 20-HETE.[25][26][27]

See also: CYP4F2 § Genetic Variants

Metabolism of Other 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 LTB4, 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.[28][29] 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 variants (SNPs) with human Crohn's disease (rs2108622)[30] and Coeliac disease (rs3093156 and rs3093156).[31][32][33][34][35]

Genetic variants

The T allele at rs2108622 (Val433Met) has a role in eicosanoid metabolism. It also has a role in affecting doses of warfarin[36] or coumarin.[9] It is also associated with increased blood pressure [37][38] and decreased Vitamin E metabolism.[39][40] It also affects the bioavailability of Vitamin K.


References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000186115 – Ensembl, May 2017
  2. ^ a b c 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.
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  6. ^ Kikuta Y, Kusunose E, Kondo T, Yamamoto S, Kinoshita H, Kusunose M (Jul 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.
  7. ^ a b "Entrez Gene: CYP4F2 cytochrome P450, family 4, subfamily F, polypeptide 2".
  8. ^ "Very Important Pharmacogene: CYP4F2".
  9. ^ a b Danese, E.; Raimondi, S.; Montagnana, M.; Tagetti, A.; Langaee, T.; Borgiani, P.; Ciccacci, C.; Carcas, A. J.; Borobia, A. M.; Tong, H. Y.; Dávila-Fajardo, C.; Rodrigues Botton, M.; Bourgeois, S.; Deloukas, P.; Caldwell, M. D.; Burmester, J. K.; Berg, R. L.; Cavallari, L. H.; Drozda, K.; Huang, M.; Zhao, L. Z.; Cen, H. J.; Gonzalez-Conejero, R.; Roldan, V.; Nakamura, Y.; Mushiroda, T.; Gong, I. Y.; Kim, R. B.; Hirai, K.; Itoh, K. (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. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  10. ^ Jin, R.; Koop, D. R.; Raucy, J. L.; Lasker, J. M. (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.
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  14. ^ Hardwick, J. P. (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.
  15. ^ Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC (Jul 2015). "Vascular actions of 20-HETE". Prostaglandins & Other Lipid Mediators. 120: 9–16. doi:10.1016/j.prostaglandins.2015.03.002. PMC 4575602. PMID 25813407.
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  19. ^ Fu, Z; Nakayama, T; Sato, N; Izumi, Y; Kasamaki, Y; Shindo, A; Ohta, M; Soma, M; Aoi, N; Sato, M; Matsumoto, K; Ozawa, Y; Ma, Y (2008). "Haplotype-based case-control study of the human CYP4F2 gene and essential hypertension in Japanese subjects". Hypertension Research. 31 (9): 1719–26. doi:10.1291/hypres.31.1719. PMID 18971550.
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  21. ^ Ward, N. C.; Croft, K. D.; Puddey, I. B.; Phillips, M; Van Bockxmeer, F; Beilin, L. J.; Barden, A. E. (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.
  22. ^ Ding, H; Cui, G; Zhang, L; Xu, Y; Bao, X; Tu, Y; Wu, B; Wang, Q; Hui, R; Wang, W; Dackor, R. T.; Kissling, G. E.; Zeldin, D. C.; Wang, D. W. (2010). "Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population". Pharmacogenetics and Genomics. 20 (3): 187–94. doi:10.1097/FPC.0b013e328336eefe. PMC 3932492. PMID 20130494.
  23. ^ Fu, Z; Nakayama, T; Sato, N; Izumi, Y; Kasamaki, Y; Shindo, A; Ohta, M; Soma, M; Aoi, N; Sato, M; Ozawa, Y; Ma, Y; Matsumoto, K; Doba, N; Hinohara, S (2009). "A haplotype of the CYP4F2 gene associated with myocardial infarction in Japanese men". Molecular Genetics and Metabolism. 96 (3): 145–7. doi:10.1016/j.ymgme.2008.11.161. PMID 19097922.
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  27. ^ Wang, T.; Xu, L. (2019). "Circulating Vitamin e Levels and Risk of Coronary Artery Disease and Myocardial Infarction: A Mendelian Randomization Study". Nutrients. 11 (9): 2153. doi:10.3390/nu11092153. PMC 6770080. PMID 31505768.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  29. ^ Hardwick, J. P. (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.
  30. ^ http://www.snpedia.com/index.php/Rs2108622
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Further reading

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