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 and hydroxylates medium-chain fatty acids such as laurate and myristate.
CYP4A11 is highly expressed in the liver and kidney.
CYP4A11 also has epoxygenase activity in that it metablizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 19,20-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ isomers). CYP4A11 does not convert arachidonic acid to epoxides. CYP4F8 and CYP4F12 likewise possess both monooxygenase activity for arachidonic acid and epoxygenase activity for docosahexaenoic and eicosapentenoic acids. In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs (16,17-EDPs, 19,20-EDPs, 17,18-EEQs have been most often examined) have actions which often oppose those of 20-HETE, principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see 20-Hydroxyeicosatetraenoic acid, Epoxyeicosatetraenoic acid, and Epoxydocosapentaenoic acid sections on activities and clinical significance). These studies also indicate that the EPAs and EEQs are: 1) more potent than the CYP450 epoxygenase (e.g. CYP2C8, CYP2C9, CYP2C19, CYP2J2, and CYP2S1)-formed epoxides of arachidonic acid (termed EETs) in decreasing hypertension and pain perception; 2) more potent than or at least equal in potency to the EETs in suppressing inflammation; and 3) act oppositely from the EETs in that they inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems. Consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans and in humans are by far the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids.
T8590C single nucleotide polymorphism (SNP), rs1126742, in the CYPA411 gene produces a protein with significantly reduced catalytic activity due to a loss-of-function mechanism; this SNP has been associated with hypertension in some but not all population studies. This result could be due to a decline in the production of EEQs and EPDs, which as indicated above, have blood pressure lowering actions.
^Palmer CN, Richardson TH, Griffin KJ, Hsu MH, Muerhoff AS, Clark JE, Johnson EF (Feb 1993). "Characterization of a cDNA encoding a human kidney, cytochrome P-450 4A fatty acid omega-hydroxylase and the cognate enzyme expressed in Escherichia coli". Biochimica et Biophysica Acta. 1172 (1-2): 161–6. doi:10.1016/0167-4781(93)90285-L. PMID7679927.
^Fu Z, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Shindo A, Ohta M, Soma M, Aoi N, Sato M, Ozawa Y, Ma Y (Mar 2008). "A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men". Journal of Hypertension. 26 (3): 453–61. doi:10.1097/HJH.0b013e3282f2f10c. PMID18300855.
^Mayer B, Lieb W, Götz A, König IR, Aherrahrou Z, Thiemig A, Holmer S, Hengstenberg C, Doering A, Loewel H, Hense HW, Schunkert H, Erdmann J (2005). "Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy". Hypertension. 46 (4): 766–71. doi:10.1161/01.HYP.0000182658.04299.15. PMID16144986.
^Sugimoto K, Akasaka H, Katsuya T, Node K, Fujisawa T, Shimaoka I, Yasuda O, Ohishi M, Ogihara T, Shimamoto K, Rakugi H (Dec 2008). "A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population". Hypertension. 52 (6): 1142–8. doi:10.1161/HYPERTENSIONAHA.108.114082. PMID18936345.
^ abFleming I (Oct 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–40. doi:10.1124/pr.113.007781. PMID25244930.
^Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M (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. PMID9675028.
^Hardwick JP (Jun 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. PMID18433732.
^Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C (2006). "A functional candidate screen for coeliac disease genes". European Journal of Human Genetics : EJHG. 14 (11): 1215–22. doi:10.1038/sj.ejhg.5201687. PMID16835590.
^Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, Amet Y, Salaün JP (2012). "Human cytochrome P450 4F3: structure, functions, and prospects". Drug Metabolism and Drug Interactions. 27 (2): 63–71. doi:10.1515/dmdi-2011-0037. PMID22706230.
^Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, Amre DK (Apr 2014). "Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease". Gastroenterology. 146 (4): 929–31. doi:10.1053/j.gastro.2013.12.034. PMID24406470.
^Zordoky, B. N.; El-Kadi, A. O. (2010). "Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases". Pharmacology & Therapeutics. 125 (3): 446–63. doi:10.1016/j.pharmthera.2009.12.002. PMID20093140.
Kawashima H, Kusunose E, Kubota I, Maekawa M, Kusunose M (Jan 1992). "Purification and NH2-terminal amino acid sequences of human and rat kidney fatty acid omega-hydroxylases". Biochimica et Biophysica Acta. 1123 (2): 156–62. doi:10.1016/0005-2760(92)90106-6. PMID1739747.
Kawashima H, Kusunose E, Kikuta Y, Kinoshita H, Tanaka S, Yamamoto S, Kishimoto T, Kusunose M (Jul 1994). "Purification and cDNA cloning of human liver CYP4A fatty acid omega-hydroxylase". Journal of Biochemistry. 116 (1): 74–80. PMID7798189.
Imaoka S, Ogawa H, Kimura S, Gonzalez FJ (Dec 1993). "Complete cDNA sequence and cDNA-directed expression of CYP4A11, a fatty acid omega-hydroxylase expressed in human kidney". DNA and Cell Biology. 12 (10): 893–9. doi:10.1089/dna.1993.12.893. PMID8274222.
Powell PK, Wolf I, Lasker JM (Nov 1996). "Identification of CYP4A11 as the major lauric acid omega-hydroxylase in human liver microsomes". Archives of Biochemistry and Biophysics. 335 (1): 219–26. doi:10.1006/abbi.1996.0501. PMID8914854.
Powell PK, Wolf I, Jin R, Lasker JM (Jun 1998). "Metabolism of arachidonic acid to 20-hydroxy-5,8,11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11". The Journal of Pharmacology and Experimental Therapeutics. 285 (3): 1327–36. PMID9618440.
Lasker JM, Chen WB, Wolf I, Bloswick BP, Wilson PD, Powell PK (Feb 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. PMID10660572.
Kawashima H, Naganuma T, Kusunose E, Kono T, Yasumoto R, Sugimura K, Kishimoto T (Jun 2000). "Human fatty acid omega-hydroxylase, CYP4A11: determination of complete genomic sequence and characterization of purified recombinant protein". Archives of Biochemistry and Biophysics. 378 (2): 333–9. doi:10.1006/abbi.2000.1831. PMID10860550.
Hoch U, Ortiz De Montellano PR (Apr 2001). "Covalently linked heme in cytochrome p4504a fatty acid hydroxylases". The Journal of Biological Chemistry. 276 (14): 11339–46. doi:10.1074/jbc.M009969200. PMID11139583.
Gonzalez MC, Marteau C, Franchi J, Migliore-Samour D (Nov 2001). "Cytochrome P450 4A11 expression in human keratinocytes: effects of ultraviolet irradiation". The British Journal of Dermatology. 145 (5): 749–57. doi:10.1046/j.1365-2133.2001.04490.x. PMID11736898.
LeBrun LA, Hoch U, Ortiz de Montellano PR (Apr 2002). "Autocatalytic mechanism and consequences of covalent heme attachment in the cytochrome P4504A family". The Journal of Biological Chemistry. 277 (15): 12755–61. doi:10.1074/jbc.M112155200. PMID11821421.
Savas U, Hsu MH, Johnson EF (Jan 2003). "Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone". Archives of Biochemistry and Biophysics. 409 (1): 212–20. doi:10.1016/S0003-9861(02)00499-X. PMID12464261.
Bellamine A, Wang Y, Waterman MR, Gainer JV, Dawson EP, Brown NJ, Capdevila JH (Jan 2003). "Characterization of the CYP4A11 gene, a second CYP4A gene in humans". Archives of Biochemistry and Biophysics. 409 (1): 221–7. doi:10.1016/S0003-9861(02)00545-3. PMID12464262.
Jin P, Fu GK, Wilson AD, Yang J, Chien D, Hawkins PR, Au-Young J, Stuve LL (Apr 2004). "PCR isolation and cloning of novel splice variant mRNAs from known drug target genes". Genomics. 83 (4): 566–71. doi:10.1016/j.ygeno.2003.09.023. PMID15028279.
Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, Ratain MJ (Sep 2004). "CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes". Drug Metabolism and Disposition. 32 (9): 930–6. PMID15319333.
Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, Cupples LA, Guo CY, Demissie S, O'Donnell CJ, Brown NJ, Waterman MR, Capdevila JH (Jan 2005). "Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension". Circulation. 111 (1): 63–9. doi:10.1161/01.CIR.0000151309.82473.59. PMID15611369.
Mayer B, Lieb W, Götz A, König IR, Aherrahrou Z, Thiemig A, Holmer S, Hengstenberg C, Doering A, Loewel H, Hense HW, Schunkert H, Erdmann J (Oct 2005). "Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy". Hypertension. 46 (4): 766–71. doi:10.1161/01.HYP.0000182658.04299.15. PMID16144986.