CYP4F3 explained

Cytochrome P450 4F3, also leukotriene-B(4) omega-hydroxylase 2, is an enzyme that in humans is encoded by the CYP4F3 gene.^{[1] [2] [3]} CYP4F3 encodes two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single pre-mRNA precursor molecule; selection of either isoform is tissue-specific with CYP3F3A being expressed mostly in leukocytes and CYP4F3B mostly in the liver.^[4]

Function

The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, fatty acids and other lipids. CYP4F3 actually encodes two splice-variants, CYP4F3A and CYP4F3B, of the cytochrome P450 superfamily of enzymes. The gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F8, is approximately 18 kb away. Both variants localize on the endoplasmic reticulum and metabolize leukotriene B4 and very likely 5-hydroxyeicosatetraenoic acid, 5-oxo-eicosatetraenoic acid, and 12-hydroxyeicosatetraenoic acid by an omega oxidation reaction, i.e. by adding a hydroxyl residue to their terminal (i.e. C-20) carbon.^[5] This addition starts the process of inactivating and degrading all of these well-known mediators of inflammation^[6] CYP3FA is the major enzyme accomplishing these omega oxidations in leukocytes.^[6]

CYP4F3A and/or CYP43FB also omega oxidize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) as well as epoxyeicosatrienoic acids (EETs) to 20-hydroxy-EETs.^[6] 20-HETE regulates blood flow, vascularization, blood pressure, and kidney tubule absorption of ions in rodents and possibly humans;^[4] it has also been proposed to be involved in regulating the growth of various types of human cancers (see). EETs have a similar set of regulatory functions but often act in a manner opposite to 20-HETE (see); since, however, the activities of the 20-HEETs have not been well-defined, the function of EET omega oxidation is unclear.^[4]

Genetic variants

The hydroxylation-induced inactivation of the mediators of inflammation, perhaps particularly of leukotriene B4, may underlie the proposed roles of these cytochromes in dampening inflammatory responses as well as the reported associations of certain CYP4F3 single nucleotide variants (SNPs) with human Crohn's disease (SNPs are designated rs1290617^[7] and rs1290620^[8] and celiac disease (rs1290622 and rs1290625).^{[4] [9] [10] [11] [12]}

There is also a study that have found an association within Guangzhou population between the single nucleotide variation rs3794987 and susceptibility to the SARS-CoV-1 virus, discovered in 2003. The GG/AG genotype was associated with an increased susceptibility to SARS-CoV-1, comparing to the AA genotype. However, the results of this association were not replicated in another study, on the Beijing population. The combined analysis of the two studies does not show any association of the CYP4F3 SNPs analyzed with SARS-CoV-1 susceptibility.^[13]

Further reading

• Simpson AE . The cytochrome P450 4 (CYP4) family . General Pharmacology . 28 . 3 . 351–9 . March 1997 . 9068972 . 10.1016/S0306-3623(96)00246-7 .
• Kikuta Y, Kusunose E, Kondo T, Yamamoto S, Kinoshita H, Kusunose M . Cloning and expression of a novel form of leukotriene B4 omega-hydroxylase from human liver . FEBS Letters . 348 . 1 . 70–4 . July 1994 . 8026587 . 10.1016/0014-5793(94)00587-7 . 83948293 . free . 1994FEBSL.348...70K .
• Christmas P, Ursino SR, Fox JW, Soberman RJ . 307381 . Expression of the CYP4F3 gene. tissue-specific splicing and alternative promoters generate high and low K(m) forms of leukotriene B(4) omega-hydroxylase . The Journal of Biological Chemistry . 274 . 30 . 21191–9 . July 1999 . 10409674 . 10.1074/jbc.274.30.21191 . free .
• Christmas P, Jones JP, Patten CJ, Rock DA, Zheng Y, Cheng SM, Weber BM, Carlesso N, Scadden DT, Rettie AE, Soberman RJ . 6 . Alternative splicing determines the function of CYP4F3 by switching substrate specificity . The Journal of Biological Chemistry . 276 . 41 . 38166–72 . October 2001 . 11461919 . 10.1074/jbc.M104818200 . free .
• Christmas P, Carlesso N, Shang H, Cheng SM, Weber BM, Preffer FI, Scadden DT, Soberman RJ . 31914930 . 6 . Myeloid expression of cytochrome P450 4F3 is determined by a lineage-specific alternative promoter . The Journal of Biological Chemistry . 278 . 27 . 25133–42 . July 2003 . 12709424 . 10.1074/jbc.M302106200 . free .
• Mizukami Y, Sumimoto H, Takeshige K . Induction of cytochrome CYP4F3A in all-trans-retinoic acid-treated HL60 cells . Biochemical and Biophysical Research Communications . 314 . 1 . 104–9 . January 2004 . 14715252 . 10.1016/j.bbrc.2003.12.062 .
• Christmas P, Tolentino K, Primo V, Berry KZ, Murphy RC, Chen M, Lee DM, Soberman RJ . 6 . Cytochrome P-450 4F18 is the leukotriene B4 omega-1/omega-2 hydroxylase in mouse polymorphonuclear leukocytes: identification as the functional orthologue of human polymorphonuclear leukocyte CYP4F3A in the down-regulation of responses to LTB4 . The Journal of Biological Chemistry . 281 . 11 . 7189–96 . March 2006 . 16380383 . 10.1074/jbc.M513101200 . free .

Notes and References

1. Kikuta Y, Kusunose E, Endo K, Yamamoto S, Sogawa K, Fujii-Kuriyama Y, Kusunose M . A novel form of cytochrome P-450 family 4 in human polymorphonuclear leukocytes. cDNA cloning and expression of leukotriene B4 omega-hydroxylase . The Journal of Biological Chemistry . 268 . 13 . 9376–80 . May 1993 . 10.1016/S0021-9258(18)98360-2 . 8486631 . free .
2. Kikuta Y, Kato M, Yamashita Y, Miyauchi Y, Tanaka K, Kamada N, Kusunose M . Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization . DNA and Cell Biology . 17 . 3 . 221–30 . March 1998 . 9539102 . 10.1089/dna.1998.17.221 .
3. Web site: Entrez Gene: CYP4F3 cytochrome P450, family 4, subfamily F, polypeptide 3.
4. Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, Amet Y, Salaün JP . 5258044 . 6 . Human cytochrome P450 4F3: structure, functions, and prospects . Drug Metabolism and Drug Interactions . 27 . 2 . 63–71 . April 2012 . 22706230 . 10.1515/dmdi-2011-0037 .
5. Powell WS, Rokach J . Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1851 . 4 . 340–55 . April 2015 . 25449650 . 5710736 . 10.1016/j.bbalip.2014.10.008 .
6. Book: Johnson AL, Edson KZ, Totah RA, Rettie AE . Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer . Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer . Advances in Pharmacology . 74 . 223–62 . 2015 . 26233909 . 10.1016/bs.apha.2015.05.002 . 4667791. 9780128031193 .
7. Web site: Rs1290617 . SNPedia .
8. Web site: Reference SNP (refSNP) Cluster Report: rs1290620 .
9. Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C . A functional candidate screen for coeliac disease genes . European Journal of Human Genetics . 14 . 11 . 1215–22 . November 2006 . 16835590 . 10.1038/sj.ejhg.5201687 . 10054589 . free .
10. Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, Amre DK . Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease . Gastroenterology . 146 . 4 . 929–31 . April 2014 . 24406470 . 10.1053/j.gastro.2013.12.034 . free .
11. Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M . 6 . Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3) . Archives of Biochemistry and Biophysics . 355 . 2 . 201–5 . July 1998 . 9675028 . 10.1006/abbi.1998.0724 .
12. Hardwick JP . Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases . Biochemical Pharmacology . 75 . 12 . 2263–75 . June 2008 . 18433732 . 10.1016/j.bcp.2008.03.004 .
13. Zhu X, Wang Y, Zhang H, Liu X, Chen T, Yang R, Shi Y, Cao W, Li P, Ma Q, Zhai Y, He F, Zhou G, Cao C . 6 . Genetic variation of the human α-2-Heremans-Schmid glycoprotein (AHSG) gene associated with the risk of SARS-CoV infection . PLOS ONE . 6 . 8 . e23730 . 2011 . 21904596 . 3163911 . 10.1371/journal.pone.0023730 . 2011PLoSO...623730Z . free .