CYP4F2
Leukotriene-B omega-hydroxylase 1 is an enzyme that in humans is encoded by the CYP4F2 gene.
Function
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.
The enzyme CYP4F2 is involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins. It 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. The enzyme also regulates 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.
Chain shortening
Fatty acids can be degraded by α, β, and ω-oxidation of their carbon chains. The preferred pathway of fatty acid degradation is β-oxidation in the mitochondria and peroxisomes. Very long chain fatty acids, which are fatty acids with more than 22 carbons in their chain, cannot be β-oxidized and must be chain-shortened before they can be oxidized by the mitochondria. CYP4F2 contributes to fatty acid oxidation by catalyzing the ω-oxidation and chain shortening of very long chain fatty acids.Production of eicosanoids
, metabolized by CYP4F2, 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 B4 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.Metabolism of vitamins
The enzyme plays an important role in vitamin metabolism by chain shortening.CYP4F2 is the only known enzyme to ω-hydroxylate Vitamin E, thus making it a critical modulator of circulating plasma Vitamin E levels. It catalyzes ω-hydroxylation of the phytyl chain of tocopherols, with preference for gamma-tocopherols over α-tocopherols, thus promoting retention of α-tocopherols in tissues.
Both types of Vitamin K can act as co-factors for γ-glutamyl carboxylase, which catalyzes the biochemical activation of proteins involved in blood clotting, and bone mineralization. CYP4F2 ω-xydroxylates and inactivates Vitamin K, which makes CYP4F2 an important negative regulator of Vitamin K levels.
Production of 20-HETE
CYP4F2 along with CYP4A22, CYP4A11, CYP4F3 and CYP2U1 also metabolize arachidonic acid to 20-Hydroxyeicosatetraenoic acid 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. The CYP4F2*3 polymorphism leads to reduced capacity to metabolize arachidonic acid to 20-HETE, but increased urinary excretion of 20-HETE. Researchers have identified at least 3 more single-nucleotide polymorphisms which may affect conversion of arachidonic acid to HETE-20.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. 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 with human Crohn's disease and Coeliac disease.Tye enzyme catalyzes ω-hydroxylation of 3-hydroxy fatty acids. It converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to ω-hydroxylated metabolites. It also contributes to the degradation of very long-chain fatty acids by catalyzing successive ω-oxidations and chain shortening.
Anti-parasitic drugs
is a pro-drug of the anti-parasitic drug . Two studies identified CYP4F2 as one of the enzymes responsible for catalyzing the first-pass biotransformation of pafuramidine to furamidine in human liver microsomes and human enteric microsomes.Genetic variants
The T allele at rs2108622, which has been designated as CYP4F2*3 in the 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, due to decrease in steady-state hepatic concentrations of the enzyme. This polymorphism, CYP4F2*3, is the most studied and most pharmacogenetically relevant. Another polymorphism, CYP4F2*2, increases specific enzyme activity for some substances.Studies have shown that CYP4F2*3 polymorphysm has a role in eicosanoid and Vitamin E metabolism, in the bioavailability of Vitamin K, in affecting doses of warfarin or coumarin, and is also associated with increased blood pressure, with increased risk of cerebral infarction and myocardial infarction.
Research
The molecular mediators, inducers and inhibitors, that regulate CYP4F2 expression, have mostly been elucidated in in vitro systems:- There have been findings that retinoic acid and saturated fatty acids, such as lauric acid and stearic acid, induce CYP4F2. Besides that, there were findings that lovastatin induce CYP4F2.
- There also have been findings that CYP4F2 is inhibited by peroxisomal proliferators, such as clofibrate, pirinixic acid, nafenopin and tibric acid; the anti-fungal drug ketoconazole, and sesamin - a molecule found in sesame oil and sesame seeds, also inhibit CYP4F2. Another study has shown that quercetin, tranylcypromine, and disulfiram also inhibit CYP4F2.
- A study has found that the following substances do not inhibit CYP4F2: brincidofovir and azoles, namely posaconazole, fluconazole, and voriconazole.