CYP4F2

Cytochrome P450 4F2
Protein structure of cytochrome P450 4F2 (leukotriene-B4 omega-hydroxylase 1) enzyme[1]
Identifiers
EC no.1.14.14.94
CAS no.90119-11-2
Alt. namesCYP4F2, 20-HETE synthase; 20-hydroxyeicosatetraenoic acid synthase; CYPIVF2; arachidonic acid omega-hydroxylase; cytochrome P450, family 4, subfamily F, polypeptide 2; cytochrome P450, subfamily IVF, polypeptide 2; cytochrome P450-LTB-omega; docosahexaenoic acid omega-hydroxylase; leucotriene-B4 ω-hydroxylase; leukotriene-B(4) 20-monooxygenase 1; leukotriene-B(4) omega-hydroxylase 1; LTB4 omega-hydroxylase; phylloquinone omega-hydroxylase CYP4F2.
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins
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[4][5]
Wikidata
View/Edit HumanView/Edit Mouse

Cytochrome P450 4F2 is a protein that in humans is encoded by the CYP4F2 gene. This protein is an enzyme, a type of protein that catalyzes (helps speed up) chemical reactions inside cells. This specific enzyme is part of the superfamily of cytochrome P450 (CYP) enzymes, and the encoding gene is part of a cluster of cytochrome P450 genes located on chromosome 19.

CYP enzymes (CYPs) function primarily as monooxygenases (that add one hydroxy group (−OH) to a molecule). CYPs are membrane-bound and expressed in many cells, but are most highly expressed in the liver. CYPs contain heme (a precursor to hemoglobin) and hence are classified as hemoproteins. CYPs are involved in cellular metabolism, hormone synthesis, sterol and cholesterol metabolism, and are critical in maintaining homeostasis, a process by which an organism can maintain internal stability while adjusting to changing external conditions. In humans, CYPs are responsible for about 80% of oxidative metabolism and 50% of the removal of commonly used medical drugs. In addition, CYPs are often disease modifying and hence are frequent drug targets.

In the case of this specific enzyme, its primary substrate (molecule upon which an enzyme acts) is leukotriene B4 (LTB4), an eicosanoid, which is an inflammatory mediator. By hydroxylating LTB4 to its inactivated form 20-hydroxy-LTB4, this enzyme helps regulate inflammation levels in the body for a proper immune response. This enzyme also metabolizes other eicosanoids, a class of compounds produced in leukocytes (white blood cells) by the oxidation of arachidonic acid to regulate immune inflammation promoters.

The other substrates for this enzyme are certain fatty acids and vitamins. The enzyme bioactivates specific prodrugs into their active metabolites (for example, it converts the prodrug pafuramidine into its active form, furamidine). Variations in the gene can affect enzymatic activity, which has implications for drug dosing and bioavailability of fat-soluble vitamins such as vitamin E and vitamin K. In particular, variations affecting vitamin K bioavailability impact the dosing of vitamin K antagonists like warfarin or coumarin.

Gene

[edit]
See also: Introduction to genetics

The cytochrome P450 4F2 protein is encoded by the CYP4F2 gene in humans.

The term "encoded" in this context means that the gene contains the information or instructions on how to make the protein. The gene is composed of a sequence of nucleotides—building blocks of DNA. The nucleotides form a code that specifies the order of amino acids, which are the building blocks of proteins. The process of converting the genetic code into a protein is called gene expression. This process involves two main steps: transcription and translation.[6] Transcription is copying the gene's DNA sequence into a messenger RNA (mRNA) molecule.[7] Translation is decoding the mRNA sequence into a protein by the ribosomes, which are cells' protein factories.[8] After transcription and translation, a protein folds into a specific shape that determines its function.[9] This shape, or conformation, is crucial as it determines the protein's function: if a protein does not fold correctly, it may not function properly or at all. Incorrect protein folding is the basis of many diseases which are associated with misfolded proteins.[10][11][12]

CYP4F2 is part of a cluster of cytochrome P450 genes located on chromosome 19, with another closely related gene, CYP4F11, located approximately 16 kbp away.[13][14]

CYP4F2 contains at least 13 exons, with its open reading frame encoded from exon II to exon XIII.[14] Exon I includes 49 bp of a 5-prime untranslated sequence.[14] This gene's structure closely resembles CYP4F3.[15]

Gene polymorphisms (variants) in CYP4F2 affect liver mRNA levels and enzymatic activity of the protein encoded.[16]

The analysis of the gene on a molecular level presents several difficulties:

  • CYP4F2 is highly polymorphic, meaning that many genetic variants are present within the population; this nature makes it challenging to identify and define specific causal variants that may be responsible for certain phenotypic effects or disease associations;
  • CYP4F2 is located within a cluster of genes of the CYP4F subfamily; these genes exhibit high homology and share similarities in their sequences that can lead to difficulties distinguishing between different members of the CYP4F subfamily during genetic analysis, including distinguishing between functional genes and pseudogenes (non-functional copies of genes) within this cluster;
  • the genes of the CYP4F subfamily tend to be closely linked on the chromosome and inherited together due to a phenomenon called linkage disequilibrium, which means that when analyzing one gene from the subfamily, it becomes challenging to differentiate its sequence from other closely related functional genes or pseudogenes within the cluster.[17][18][16]

Protein

[edit]
See also: Protein folding

Proteins consist of amino acid residues and form a three-dimensional structure. Yet, the exact arrangement of atoms, also known as the crystal structure, of the enzyme CYP4F2 has not been determined. Still, researchers employ homology modeling, a method that uses the structures of similar enzymes as a template, to construct a theoretical model of CYP4F2's structure. Additionally, molecular docking has been employed to create a complex model of how CYP4F2 interacts with its substrates, to predict how the enzyme functions even without knowing its exact structure.[19]

Species

[edit]
See also: Introduction to evolution

The CYP4F2 gene is widely expressed in vertebrates, including mammals, birds (Aves), amphibians (Amphibia), and ray-finned fishes (Actinopterygii); it has been identified and studied to gain insights into its evolutionary conservation across these diverse vertebrate classes.[20]

As of 2024, information regarding the presence or functional characteristics of the gene in other animal groups, such as invertebrates, is limited. Some studies have examined genes of CYP4 family in major invertebrate classes like Ascidiacea, Echinoidea, Gastropoda, and Insecta. Still, specific information about the existence of CYP4F2 specifically within these groups is not widely available.[20][21]

It is assumed that CYP4 enzymes from the same subfamily have similar functions in different vertebrate species, but this assumption may not be valid, as CYP4 enzymes may have diverged in their functions, biochemical properties, and gene expression patterns over evolutionary time. To test the functional hypotheses of CYP4 enzymes in non-mammalian vertebrates, researchers can use computational methods that compare the sequences, structures, and interactions of CYP4 proteins from different species. These methods can help to identify the functional divergence, the radical biochemical changes, and the gene expression patterns.[20]

For example, one study used a computational approach to predict that the Cyp4d2 in a fruit fly (drosophila melanogaster), which is an ortholog of the human CYP4F2, may be involved in the metabolism of insect hormones and in the breakdown of synthetic insecticides.[22] An ortholog is a gene that is related by common ancestry and has the same function in different species.[23] The Cyp4d2 in the fruit fly is expressed in the malpighian tubules, which are the insect equivalent of the kidneys, and may play a role in detoxification and osmoregulation.[22] The human CYP4F2, on the other hand, is mostly expressed in the liver, duodenum, small intestine, and the kidney, and is involved in the metabolism of eicosanoids and vitamin K. Eicosanoids are a class of compounds produced in leukocytes (white blood cells) by the oxidation of arachidonic acid to regulate the immune response.[24]

Tissue and subcellular distribution

[edit]

In humans, CYP4F2 is expressed in various tissues, including the liver, duodenum, small intestine, kidney, bone marrow, epididymis, and prostate,[25] with the highest expression in the liver.[26] CYP4F2 expression can be influenced by various factors, such as genetic variations, dietary intake, drug interactions, and inflammatory conditions.[27]

The CYP4F2 protein localizes to the endoplasmic reticulum (ER) of an eukariotic cell.[13] As of 2024, the main subcellular location for the encoded protein CYP4F2 in human cells is not known, and is pending cell analysis.[28] ER is a continuous membrane system that forms a series of flattened sacs within the cytoplasm. The ER is divided into two domains: the rough ER, which is studded with ribosomes and is involved in protein synthesis, and the smooth ER, which is devoid of ribosomes and is involved in lipid synthesis, steroid hormone production, detoxification, and calcium storage. CYP4F2 belongs to the cytochrome P450 superfamily of enzymes which are located in the membrane of the smooth ER, where they interact with electron transfer partners, such as NADPH–cytochrome P450 reductase and cytochrome b5.[14][13] The localization of CYP4F2 to the smooth ER is important for its function and regulation, as it allows the enzyme to access its substrates and cofactors, and to be modulated by various factors, such as drugs, hormones, and dietary components.[13]

Function

[edit]

The cytochrome P450 superfamily

[edit]
See also: Cytochrome P450

CYP4F2 is a member of the cytochrome P450 (CYP) superfamily of enzymes.[13]

Generally, CYP enzymes are a type of protein bound to the membranes of cells, meaning they are attached to the outer layer of a cell.[14][29] They are found in many types of cells throughout the human body, but are particularly abundant in the liver. These enzymes are classified as hemoproteins, a group of proteins that contain heme, an iron-containing compound that carries oxygen. In the clinical sciences they play critical roles in the detoxification of drugs, that is the process of breakdown and removing toxic substances from the body.[30] CYP enzymes are involved in cellular metabolism, hormone synthesis, sterol and cholesterol metabolism, and are critical in maintaining homeostasis, the body's a natural ability to maintain balanced internal environment despite external changes.[14][29][30][31] Sterols are a type of lipid, or fat, and cholesterol is a specific type of sterol that is crucial for the body's function. In humans, a significant portion of the body's metabolic processes, specifically around 80%,[32] involve oxidative metabolism, which generally makes the substrate more water-soluble and so more readily excreted by the kidneys.[30][33] CYP enzymes also play a crucial role in the elimination of drugs from the body. Approximately 50% of the breakdown and removal of common drugs used in clinical medicine can be attributed to one or more of these CYP enzymes.[29] This function is vital in ensuring that drugs are effectively used and subsequently removed from the body to prevent any potential harm.[30][29][14]

Due to their role in many biological processes such as vascular constriction, sex hormone biosynthesis, and inflammatory response, CYP enzymes can be affected by therapy with the aim of modifying the course of diseases, a concept known as disease-modifying treatment. Because of this role, they are frequently targeted in drug development, a process referred to as identifying biological targets.[34][35][36]

The CYP4F subfamily

[edit]

The CYP4F subfamily of CYP enzymes exhibits diverse metabolic specificities, but is characterized by the ω-hydroxylation of very long-chain fatty acids (VLCFA), eicosanoids, lipophilic (fat-soluble) vitamins, and hydroxyeicosatetraenoic acids (HETEs).[20] The cytochrome P450 4F2 protein is an enzyme also known as "leukotriene-B4 ω-hydroxylase 1", because it starts the process of inactivating and degrading leukotriene B4 (LTB4), a potent mediator of inflammation, by ω-hydroxylating it to 20-hydroxy-LTB4.[13]

CYP4F2 and CYP4F3 catalyze the ω-hydroxylation of pro- and anti-inflammatory leukotrienes, modulating their biological activities.[15][20] CYP4F8 and CYP4F12 are involved in the metabolism of prostaglandins, endoperoxides, and arachidonic acid, regulating their inflammatory and vascular effects.[20] CYP4F11 and CYP4F12 also metabolize VLCFA and display a unique feature in the CYP4F subfamily, as they are able to hydroxylate xenobiotics such as certain amphetamines, opioids, and macrolide antibiotics.[37][20] As of 2024, the functional roles of CYP4X and CYP4Z subfamilies remains not fully characterized.[14][21] CYP4X gene expression is predominantly associated with the brain and the neurovascular regions, suggesting involvement in neurological disorders. CYP4Z is mainly expressed in the mammary gland, and its expression is up-regulated in breast cancer, implying a role in tumorigenesis.[37][14][20] The CYP4 family of genes is characterized by a wide range of physiological functions of the enzymes and varied gene expression patterns. However, despite this diversity, there is a notable consistency in the structure of the substrates they act upon. This implies that while each enzyme within the CYP4 family may perform different tasks and be expressed differently, they all interact with similar types of substrates.[20]

The CYP4F subfamily plays a role in the development of cancer. Enzymes such as CYP4F2 and CYP4F3B convert arachidonic acid into 20-Hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid metabolite of arachidonic acid. This metabolite has crucial impacts on the progression of tumors, the formation of new blood vessels (angiogenesis), and the regulation of blood pressure in blood vessels and kidneys.[36][38]

CYP4F2 within the subfamily

[edit]

As for the CYP4F2, besides its role in degrading LTB4, this enzyme is also involved in the metabolism of various endogenous substrates such as fatty acids, eicosanoids, and numerous fat-soluble vitamins.[39]

It controls the bioavailability of vitamin E.[40]

The enzyme also controls the bioavailability of Vitamin K, a co-factor required for blood to clot.[41]

Gene polymorphisms (variations) in the CYP4F2 affect enzymatic activity, i.e., the ability of the enzyme to metabolize its substrates.[41] The variations in the gene which affect the bioavailability of vitamin K also affect the dosing of vitamin K antagonists such as warfarin,[41][42][43] coumarin, or acenocoumarol.[44][45]

The enzyme also regulates the bioactivation of certain drugs, such as the anti-parasitic prodrug pafuramidine, into its active form, furamidine, by catalyzing the initial oxidative O-demethylation of pafuramidine by human liver microsomes. Pafuramidine could undergo first-pass biotransformation in the intestine, as well as in the liver.[46][47][48]

The enzyme also plays a role in renal water homeostasis.[49]

Metabolism of leukotriene B4

[edit]

Biosynthesis of leukotriene B4 from arachidonic acid

[edit]

Leukotriene B4 (LTB4) is a type of lipid mediator that belongs to the family of leukotrienes, which are derived from arachidonic acid by the action of 5-lipoxygenase (5-LOX).[50]

Arachidonic acid is a polyunsaturated fatty acid that is present in the phospholipids of cell membranes. It can be released from the membrane by the action of phospholipase A2, a peripheral membrane protein, which is activated by stimuli such as hormones, cytokines, growth factors and stress. Arachidonic acid can then be metabolized by three major pathways: the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway, and the cytochrome P450 (CYP) pathway.[51] These pathways produce different types of lipid mediators, which are collectively called eicosanoids.[50]

Eicosanoids are a group of bioactive molecules that have diverse and potent effects on physiological and pathological processes such as inflammation, immunity, pain, fever, blood pressure, blood clotting, reproduction and cancer. There are multiple types of eicosanoids, such as prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids (HETEs), and so on.[24]

Leukotriene B4 (LTB4) is one of the eicosanoids that is produced by the LOX pathway. It is synthesized from arachidonic acid by the sequential actions of 5-LOX, 5-LOX activating protein (FLAP), and leukotriene A4 hydrolase (LTA4H).[50]

LTB4 is produced by activated innate immune cells, such as neutrophils, macrophages and mast cells.[52][50] It induces the activation of polymorphonuclear leukocytes, monocytes and fibroblasts, the production of superoxide and the release of cytokines to attract neutrophils.[53][54][55]

The role of leukotriene B4 in inflammatory response

[edit]

LTB4 plays a key role in the initiation and maintenance of inflammation, as it can recruit and activate immune cells such as neutrophils, macrophages, mast cells, monocytes and fibroblasts. LTB4 also stimulates the production of reactive oxygen species, cytokines, chemokines and adhesion molecules, which further amplify the inflammatory response.[56][57]

Inactivation of leukotriene B4 by CYP4F2

[edit]
Hydroxylation of Leukotriene B4 catalyzed by CYP4F2

Excessive or prolonged inflammation can be harmful to the host, as it can cause tissue damage and chronic diseases, so that the inflammatory process must be tightly regulated and resolved in a timely manner. One of the mechanisms that contributes to the resolution of inflammation is the enzymatic inactivation and degradation of LTB4 by the cytochrome P450 (CYP) family of enzymes. CYP enzymes are mainly expressed in the liver, but they can also be found in other tissues, such as the lungs, kidneys, intestines, and skin.[58][59]

Among the CYP enzymes, CYP4F2 is the most important one for the metabolism of LTB4.[37][14][60]

CYP4F2 catalyzes the ω-hydroxylation of LTB4, which is the first step of its inactivation and degradation. It converts LTB4 to 20-hydroxy-LTB4, which has much lower biological activity.[61]

CYP4F2 then coverts 20-hydroxy-LTB4 to 20-oxo-LTB4 and then to 20-carboxy-LTB4,[61] which are both inactive and can be excreted from the body.[62][15]

Fatty acid ω-hydroxylation

[edit]
See also: Cytochrome P450 omega hydroxylase

CYP4F2 belongs to cytochrome P450 omega hydroxylase set of enzymes that catalyze the addition of a hydroxy functional group (−OH) to a molecule of the fatty acid substrate. Specifically, CYP4F2 performs ω-hydroxylation of fatty acids, which means that the functional group is added to the ω- or (ω-1)-C atom. In the context of fatty acids, the ω (omega) atom refers to the carbon atom at the end of the hydrocarbon chain, furthest from the carboxyl group, so that the ω- or (ω-1)-C atom refers to the last carbon atom or the second-to-last carbon atom in the hydrocarbon chain of the fatty acid: the hydroxy group is added to one of these atoms during the ω-hydroxylation process.[62]

The enzymes which are members of the CYP4A and CYP4F sub-families, including CYP4F2, may ω-hydroxylate and thereby reduce the activity of fatty acid metabolites of arachidonic acid such as LTB4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins. These enzymatic reactions lead to the production of metabolites involved in regulating inflammatory and vascular responses in animals and humans.[61][55] By reducing the activity of these fatty acid metabolites, ω-hydroxylation plays a role in dampening inflammatory pathways and maintaining immune system balance.[55]

Certain single-nucleotide polymorphisms (SNPs) in the CYP4F2 have been associated with human diseases like Crohn's disease[63][64] and Coeliac disease.[55][65][15] These genetic variations may impact the function or expression level of the enzyme, influencing its ability to perform ω-hydroxylation reactions effectively.[15]

The CYP4F2 enzyme also catalyzes ω-hydroxylation of 3-hydroxy fatty acids.[66] It converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to ω-hydroxylated metabolites.[67] By ω-hydroxylating 3-hydroxy fatty acids, the enzyme contributes to the modification of these molecules, which can have implications for their signaling functions in cellular processes. The production of ω-hydroxylated metabolites from monoepoxides derived from linoleic acid leukotoxin and isoleukotoxin helps regulate inflammation by reducing their activity as pro-inflammatory mediators.[66][67]

The enzyme also contributes to the degradation of VLCFAs by catalyzing successive ω-oxidations and chain shortening. This enzymatic activity ensures efficient breakdown and clearance of these fatty acids, preventing accumulation that could lead to metabolic imbalances or contribute to disease pathology.[68][69]

Fatty acid chain shortening

[edit]

The process of chain shortening refers to the modification of a fatty acid molecule by removing carbon atoms from its chain. Fatty acids are organic molecules consisting of a long hydrocarbon chain, typically with an even number of carbon atoms. These chains can vary in length, and their length affects their biological activities. CYP4F2 acts on fatty acids and introduces oxidative reactions that lead to the removal of carbon atoms from the chain. This process is often accompanied by the addition of oxygen to the fatty acid molecule, resulting in the formation of metabolites or breakdown products. By shortening the fatty acid chains, the CYP4F2 enzyme plays a role in vitamin metabolism. This process can affect the bioavailability, transportation, and utilization of certain fat-soluble vitamins in the body. The specific impact of chain shortening on vitamin metabolism may vary depending on the specific fatty acid and vitamin involved. This process is essential for maintaining lipid homeostasis and regulating biological activities influenced by fatty acids.[46]

Fatty acid chain shortening by CYP4F2 is performed by their α-, β-, and ω-oxidation, with the preferred pathway being the β-oxidation in the mitochondria and peroxisomes. VLCFAs 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.[46]

Additionally, the CYP4F2 enzyme plays a significant role in mediating the metabolism of long-chain polyunsaturated fatty acids (PUFAs), such as ω−3 and ω−6 fatty acids, which are required for physiological processes such as brain development, inflammation modulation, and cardiovascular health.[46]

Metabolism of vitamins

[edit]

The enzyme plays its role in metabolism of vitamins E and K by chain shortening,[70][71] i.e., by reducing the number of carbon atoms in certain hydrocarbon chains of the molecules of the vitamin, depending on a particular vitamin molecule. This process is also known as ω-hydroxylation, because it involves adding a hydroxy group (-OH) to the last carbon atom (omega position) of the chain. This makes the vitamin molecule more polar and less stable, and facilitates its further degradation by other enzymes.[72][73]

CYP4F2 is the only known enzyme to ω-hydroxylate tocotrienols and tocopherols which are forms (vitamers) of vitamin E, thus making it a key regulator of circulating plasma vitamin E levels.[74][55][75] It catalyzes ω-hydroxylation of the phytyl chain of tocopherols, with preference for γ-tocopherols over α-tocopherols, thus promoting retention of α-tocopherols in tissues.[76]

Vitamin E is a collective term for eight different molecules that have antioxidant properties and protect cell membranes from oxidative damage. They are divided into two groups: tocotrienols and tocopherols. Both groups have a chromanol ring, which is the active part of the molecule, and a phytyl chain, which is a long hydrocarbon tail. CYP4F2 shortens the phytyl chain of both tocopherols and tocotrienols by ω-hydroxylation, which reduces their biological activity and stability.[76]

Vitamin K is a collective term for two natural forms of vitamin K: vitamin K1 (phylloquinone) and vitamin K2 (menaquinone).[14][77][78] Vitamin K is essential for the synthesis of several proteins involved in blood clotting and bone metabolism.[14][77] Vitamin K1 has a phytyl chain, similar to vitamin E, while vitamin K2 has an isoprenoid chain, which is a series of five-carbon units. CYP4F2 shortens the phytyl chain of vitamin K1 and the isoprenoid chain of vitamin K2 by ω-hydroxylation, which reduces their biological activity and stability.[77]

Both types of Vitamin K (K1 and K2) can be used as co-factors for γ-glutamyl carboxylase, an enzyme that catalyzes the post-translational modification of Vitamin K-dependent proteins, thus biochemically activating the proteins involved in blood coagulation and bone mineralization.

CYP4F2 plays a pivotal role in modulating circulating levels of vitamin K1 by ω-hydroxylating and deactivating it. In the liver, where this enzyme is predominantly expressed, it functions as a primary oxidase responsible for metabolizing vitamin K1 into hydroxylated forms. By doing so, it acts synergistically with VKORC1 to prevent excessive accumulation of biologically active vitamin K in. Termed the "siphoning" pathway,[17] this mechanism primarily occurs when there is an excess amount of vitamin K1 present. This enzymatic process positions CYP4F2 as a critical negative regulator for maintaining appropriate levels of active vitamin K1 within the body.[77][79]

Biosynthesis of 20-HETE

[edit]

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.[15]

One of the main roles of 20-HETE is to regulate various physiological processes within the body, such as blood flow, vascularization, blood pressure, and kidney tubule absorption of ions in rodents and possibly humans.[80] By controlling blood flow and vascularization, it helps with the formation of new blood vessels when needed. To influence blood pressure levels, it regulates the diameter of blood vessels and constriction or relaxation of smooth muscles that line them. To regulate ion transport and water reabsorption in kidney tubules, it regulates how ions are absorbed or excreted by kidney cells, ultimately impacting electrolyte balance within the bodies. Research on animal models suggests that changes in levels or activity of 20-HETE may be involved in conditions such as hypertension (high blood pressure), renal diseases (kidney disorders), cerebral ischemia (reduced blood flow to the brain), and even cancer progression.[81][82][83]

The production and actions of 20-HETE can be influenced by genetic variations known in the CYP4F2 gene. These variations may alter how efficiently arachidonic acid is converted into 20-HETE, affecting its overall impact on bodily functions.[84]

Drug metabolism

[edit]

Drug metabolism is a crucial process in the body that involves the breakdown and transformation of drugs into their active or inactive forms. The CYP4F2 enzyme plays a significant role in regulating the bioactivation of certain drugs.[43]

Specifically, the enzyme regulates the bioactivation of the anti-parasitic drug pafuramidine. Pafuramidine is a prodrug of furamidine, which means that pafuramidine requires enzymatic conversion to its bioactive form furamidine. Several studies have identified CYP4F2 as one of the key enzymes responsible for this conversion process in human liver microsomes and enteric microsomes.[85][86]

CYP4F2 is also involved in metabolism of fingolimod, a drug to treat multiple sclerosis.[87]

Clinical significance

[edit]

Genetic variants

[edit]

Genetic variations in CYP4F2 play a role in physiological processes and health outcomes.[41] Genetic variations in CYP4F2 are considered in personalized treatments related to drug dosages and vitamin supplementation strategies.[88]

Confirmed variations in in CYP4F2 serve as biomarkers for individual differences in response to warfarin—adjusting warfarin dosage based on genetic information has demonstrated a decrease in negative clinical outcomes.[89]

Warfarin dosing algorithms that specifically incorporate the CYP4F2 genetic variants are a subset of the broader range of warfarin dosing algorithms. As of May 2020, 92 out of 433 described warfarin dosing algorithms in the literature included CYP4F2 variants; the other covariates included in these algorithms have been age, concomitant medications, weight, and the variants in the other genes: CYP2C9 and VKORC1.[89]

One specific genetic variant which produces the enzyme with valine residue replaced to methionine residue at position 433 of the protein (V433M substitution), a single-nucleotide polymorphism denoted as CYP4F2*3[90] (rs2108622),[91] that is present in 28% of global population,[92] leads to reduced enzymetic activity due to decrease in steady-state hepatic concentrations of the enzyme.[45][40] This variant has a role in eicosanoid and Vitamin E metabolism,[75][93][40] in the bioavailability of Vitamin K,[77] in affecting doses of antigoagulants such as warfarin[41][16] or coumarin,[45] and is also associated with hypertension,[94][95] with increased risk of cerebral infarction (i.e. ischemic stroke) and myocardial infarction.[83] Individuals who carry this genetic variant, either in a homozygous form (on one chromosome) or heterozygous form (on both chromosomes), may have an increased risk of excessive anticoagulation when treated with warfarin, although not all studies confirm this association.[96] This variant accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects.[89] Most of the studies on warfarin pharmacogenetics, including those involving CYP4F2, have been conducted in European ancestry patients; still, there has been significant activity in developing dosing algorithms for individuals of Asian ancestry.[89]

The CYP4F2 enzyme also regulates the bioactivation of anti-parasitic drug pafuramidine; as such, genetic variations in the CYP4F2 that alter enzyme function can impact the efficacy and safety of these drugs for patients receiving therapy. For example, individuals with a variation that leads to reduced activity of the enzyme may not fully metabolize pafuramidine, leading to lower drug concentrations and reducing its effectiveness against malaria. In contrast, variations associated with increased enzyme activity could result in faster metabolism of pafuramidine and furamidine, leading to higher than expected drug concentrations which may increase the risk of adverse effects.[46]

Drug interactions

[edit]

There can be interactions between the drugs that rely on CYP4F2 on their metabolism or bioactivation (e.g., fingolimod, furamidine, warfarin)[87][97] and the substances that inhibit or induce CYP4F2 expression, such as statins and peroxisomal proliferators (drugs to lower low-density lipoproteins and reduce risk of risk of cardiovascular disease), 25-hydroxycholesterol, vitamin K, ketoconazole (an antifungal medication), sesamin (a component of sesame oil), and others.[46]

For instance, the use of ketoconazole, which is a CYP4F2 inhibitor, has been observed to cause an increase in the concentrations of fingolimod.[87]

Biological target

[edit]

CYP4F2, along with the other enzymes that convert arachidonic acid to 20-HETE, can be a drug target in disease-modifying therapy for cancer. 20-HETE is a molecule that affects tumor progression, angiogenesis, and blood pressure regulation in the circulatory system and kidneys.[14][36] In the tumor microenvironment, proinflammatory cytokines can induce or inhibit CYP4F2 and other enzymes, which can promote carcinogenesis and affect chemotherapy, leading to adverse effects, toxicity, or therapeutic failure.[98][99] CYP enzymes could be targeted to modify the course of diseases like cancer.[100] Targeting CYPs in preclinical and clinical trials for chemoprevention and chemotherapy has become an effective way to improve antitumor treatment outcomes.[101] Intratumoral CYP enzymes can play a role in the fate of antitumor agents by drug activation or inactivation.[102] Still, they can also provide a mechanism for drug resistance due to their aberrant expression and their supporting roles in tumor progression and metastasis.[35][14]

History

[edit]

In 1997, Heng et al. found that the human CYP4F2 gene is mapped to chromosome 19 based on analysis of monochromosomal human-rodent cell hybrids using PCR.[103]

In 1999, Kikuta et al. isolated the CYP4F2 gene and determined its genomic organization and the functional activity of its promoters. The study found that the CYP4F2 gene contains at least 13 exons, with its open reading frame being encoded from exon II to exon XIII. The structure of this gene was found to be very similar to that of CYP4F3. The study also reported that CYP4F2 is constitutively expressed in a human hepatoma cell line, HepG2, and is not induced by clofibrate. The study also observed that the human liver CYP4F2 protein plays a role in the metabolic inactivation and degradation of LTB4, a mediator of inflammation.[104][14]

In 2007, Stec et al. identified a SNP in the coding region of the CYP4F2 gene, resulting in a V433M substitution, denoted as CYP4F2*3, that was frequent in both African and European American samples (9 to 21% minor allele frequency). In vitro functional expression assays indicated that the V433M variant decreased 20-HETE production levels to 56 to 66% of control levels. In contrast, the variant had no effect on the ω-hydroxylation of LTB4. The study also reported that CYP4F2 also encodes for the major CYP enzyme responsible for the synthesis of 20-HETE in the human kidney. The study found that 20-HETE plays an important role in the regulation of renal tubular and vascular function.[54][14][38]

In 2008, Caldwell et al., referring to the V433M variant as rs2108622, indicated that it affects warfarin therapy.[103][14]

In 2010, Ross et al. genotyped 963 individuals from 7 geographic regions worldwide for the CYP4F2 V433M substitution, to understand better algorithms for warfarin dose adjustment.[18][14]

In 2023, Farajzadeh-Dehkordi et al. utilized computational analysis to investigate the V433M substitution and its association with human CYP4F2 enzyme dysfunction, using computer-based methods and bioinformatics tools to analyze complex biological data, employing 14 different bioinformatics tools. The results demonstrated that this genetic variant affects the dynamics and stability of the protein biomolecule by reducing its compactness and stability, leading to alterations in overall structural conformation and flexibility.[17]

References

[edit]
  1. ^ "Computed structure model of Cytochrome P450 4F2". RCSB Protein Data Bank. 30 September 2022. AF_AFP78329F1. Archived from the original on 26 November 2023. Retrieved 26 November 2023. Structure of heme (represented as spheres) copied from PDB: 6C94​ after alignment to AF_AFP78329F1.
  2. ^ a b c GRCh38: Ensembl release 89: ENSG00000186115 – Ensembl, May 2017
  3. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003484 – Ensembl, May 2017
  4. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  6. ^ "How do genes direct the production of proteins?: MedlinePlus Genetics". medlineplus.gov. Archived from the original on 25 November 2023. Retrieved 25 November 2023.
  7. ^ "Gene Expression". Genome.gov. Archived from the original on 25 November 2023. Retrieved 25 November 2023.
  8. ^ "Translation: DNA to mRNA to Protein". Learn Science at Scitable. Archived from the original on 11 October 2023. Retrieved 25 November 2023.
  9. ^ Alberts B (2002). "The Shape and Structure of Proteins". Molecular Biology of the Cell (4th ed.). Garland Science. NCBI NBK26830.
  10. ^ Cieplak AS (2017). "Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions". PLOS ONE. 12 (9): e0180905. Bibcode:2017PLoSO..1280905C. doi:10.1371/journal.pone.0180905. PMC 5603215. PMID 28922400.
  11. ^ Ghozlan H, Cox A, Nierenberg D, King S, Khaled AR (2022). "The TRiCky Business of Protein Folding in Health and Disease". Front Cell Dev Biol. 10: 906530. doi:10.3389/fcell.2022.906530. PMC 9117761. PMID 35602608.
  12. ^ Vila JA (April 2023). "Rethinking the protein folding problem from a new perspective". Eur Biophys J. 52 (3): 189–193. arXiv:2210.05004. doi:10.1007/s00249-023-01657-w. PMID 37165178. S2CID 252815742.
  13. ^ a b c d e f Public Domain This article incorporates public domain material from "CYP4F2 cytochrome P450 family 4 subfamily F member 2". Reference Sequence collection. 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 that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. 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 subfamily, CYP4F11, is approximately 16 kbp away. Public Domain This article incorporates text from this source, which is in the public domain.
  14. ^ a b c d e f g h i j k l m n o p q r Online Mendelian Inheritance in Man (OMIM): 604426
  15. ^ a b c d e f Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, Amet Y, Salaün JP (April 2012). "Human cytochrome P450 4F3: structure, functions, and prospects". Drug Metabol Drug Interact. 27 (2): 63–71. doi:10.1515/dmdi-2011-0037. PMID 22706230. S2CID 5258044.
  16. ^ a b c Zhang JE, Klein K, Jorgensen AL, Francis B, Alfirevic A, Bourgeois S, et al. (2017). "Effect of Genetic Variability in the CYP4F2, CYP4F11, and CYP4F12 Genes on Liver mRNA Levels and Warfarin Response". Frontiers in Pharmacology. 8: 323. doi:10.3389/fphar.2017.00323. PMC 5449482. PMID 28620303.
  17. ^ a b c Farajzadeh-Dehkordi M, Mafakher L, Samiee-Rad F, Rahmani B (May 2023). "Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact". BMC Molecular and Cell Biology. 24 (1): 17. doi:10.1186/s12860-023-00479-0. PMC 10170697. PMID 37161313.
  18. ^ a b Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. (April 2008). "CYP4F2 genetic variant alters required warfarin dose". Blood. 111 (8): 4106–4112. doi:10.1182/blood-2007-11-122010. PMC 2288721. PMID 18250228.
  19. ^ Liang L, Zheng Q (April 2023). "Insights into the binding mechanism between α-TOH and CYP4F2: A homology modeling, molecular docking, and molecular dynamics simulation study". J Cell Biochem. 124 (4): 573–585. doi:10.1002/jcb.30391. PMID 36924012. S2CID 257580960.
  20. ^ a b c d e f g h i Kirischian NL, Wilson JY (January 2012). "Phylogenetic and functional analyses of the cytochrome P450 family 4". Molecular Phylogenetics and Evolution. 62 (1): 458–471. Bibcode:2012MolPE..62..458K. doi:10.1016/j.ympev.2011.10.016. PMID 22079551.
  21. ^ a b Liu J, Machalz D, Wolber G, Sorensen EJ, Bureik M (January 2021). "New Proluciferin Substrates for Human CYP4 Family Enzymes". Applied Biochemistry and Biotechnology. 193 (1): 218–237. doi:10.1007/s12010-020-03388-6. PMID 32869209. S2CID 221381798.
  22. ^ a b "UniProt". Archived from the original on 25 November 2023. Retrieved 25 November 2023.
  23. ^ Koonin EV (2005). "Orthologs, paralogs, and evolutionary genomics". Annual Review of Genetics. 39: 309–338. doi:10.1146/annurev.genet.39.073003.114725. PMID 16285863. Archived from the original on 8 August 2020. Retrieved 25 November 2023.
  24. ^ a b Calder PC (September 2020). "Eicosanoids" (PDF). Essays Biochem. 64 (3): 423–441. doi:10.1042/EBC20190083. PMID 32808658. S2CID 221162836. Archived (PDF) from the original on 25 November 2023. Retrieved 25 November 2023.
  25. ^ "CYP4F2 protein expression summary". The Human Protein Atlas. Archived from the original on 25 November 2023. Retrieved 25 November 2023.
  26. ^ Kikuta Y, Kusunose E, Kusunose M (August 2002). "Prostaglandin and leukotriene omega-hydroxylases". Prostaglandins & Other Lipid Mediators. 68: 345–362. doi:10.1016/s0090-6980(02)00039-4. PMID 12432928.
  27. ^ Grangeon A, Clermont V, Barama A, Gaudette F, Turgeon J, Michaud V (November 2021). "Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics". International Journal of Molecular Sciences. 22 (23): 12791. doi:10.3390/ijms222312791. PMC 8657875. PMID 34884595.
  28. ^ "CYP4F2 Subcellular RNA expression". The Human Protein Atlas. Archived from the original on 25 November 2023. Retrieved 25 November 2023.
  29. ^ a b c d Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, Huai C, Shen L, Zhang N, He L, Qin S (November 2021). "Cytochrome P450 Enzymes and Drug Metabolism in Humans". Int J Mol Sci. 22 (23): 12808. doi:10.3390/ijms222312808. PMC 8657965. PMID 34884615.
  30. ^ a b c d Korzekwa K (2014). "Enzyme Kinetics of Oxidative Metabolism: Cytochromes P450". Enzyme Kinetics in Drug Metabolism. Methods in Molecular Biology. Vol. 1113. Humana Press. pp. 149–166. doi:10.1007/978-1-62703-758-7_8. ISBN 978-1-62703-757-0. ISSN 1940-6029. PMID 24523112.
  31. ^ "Homeostasis | Definition, Function, Examples, & Facts | Britannica". 17 November 2023. Archived from the original on 19 August 2020. Retrieved 26 November 2023.
  32. ^ Wang X, Rao J, Tan Z, Xun T, Zhao J, Yang X (2022). "Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes". Front Pharmacol. 13: 1043836. doi:10.3389/fphar.2022.1043836. PMC 9637984. PMID 36353494.
  33. ^ Manikandan P, Nagini S (2018). "Cytochrome P450 Structure, Function and Clinical Significance: A Review". Curr Drug Targets. 19 (1): 38–54. doi:10.2174/1389450118666170125144557. PMID 28124606.
  34. ^ Guengerich FP (October 2023). "Cytochrome P450 enzymes as drug targets in human disease". Drug Metab Dispos. 52 (6): 493–497. doi:10.1124/dmd.123.001431. PMC 11114603. PMID 37793784. S2CID 263675700.
  35. ^ a b Song Y, Li C, Liu G, Liu R, Chen Y, Li W, Cao Z, Zhao B, Lu C, Liu Y (May 2021). "Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes". Clin Pharmacokinet. 60 (5): 585–601. doi:10.1007/s40262-021-01001-5. PMID 33723723. S2CID 232237738.
  36. ^ a b c Stipp MC, Acco A (March 2021). "Involvement of cytochrome P450 enzymes in inflammation and cancer: a review". Cancer Chemother Pharmacol. 87 (3): 295–309. doi:10.1007/s00280-020-04181-2. PMID 33112969. S2CID 225080314.
  37. ^ a b c Jarrar YB, Lee SJ (August 2019). "Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications". Int J Mol Sci. 20 (17): 4274. doi:10.3390/ijms20174274. PMC 6747359. PMID 31480463.
  38. ^ a b Ni KD, Liu JY (2021). "The Functions of Cytochrome P450 ω-hydroxylases and the Associated Eicosanoids in Inflammation-Related Diseases". Front Pharmacol. 12: 716801. doi:10.3389/fphar.2021.716801. PMC 8476763. PMID 34594219.
  39. ^ "CYP4F2 Gene". Archived from the original on 6 August 2020. Retrieved 3 July 2020.
  40. ^ a b c Schmölz L, Birringer M, Lorkowski S, Wallert M (February 2016). "Complexity of vitamin E metabolism". World Journal of Biological Chemistry. 7 (1): 14–43. doi:10.4331/wjbc.v7.i1.14. PMC 4768118. PMID 26981194.
  41. ^ a b c d e Asiimwe IG, Zhang EJ, Osanlou R, Jorgensen AL, Pirmohamed M (April 2021). "Warfarin dosing algorithms: A systematic review". British Journal of Clinical Pharmacology. 87 (4): 1717–1729. doi:10.1111/bcp.14608. PMC 8056736. PMID 33080066.
  42. ^ Zhao Z, Zhao F, Wang X, Liu D, Liu J, Zhang Y, et al. (June 2023). "Genetic Factors Influencing Warfarin Dose in Han Chinese Population: A Systematic Review and Meta-Analysis of Cohort Studies". Clinical Pharmacokinetics. 62 (6): 819–833. doi:10.1007/s40262-023-01258-y. PMID 37273173. S2CID 259073998.
  43. ^ a b Sridharan K, Sivaramakrishnan G (June 2021). "A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional". Journal of Clinical Pharmacy and Therapeutics. 46 (3): 640–648. doi:10.1111/jcpt.13334. PMID 33346393. S2CID 229342467.
  44. ^ "Very Important Pharmacogene: CYP4F2". PharmGKB. Stanford University. Archived from the original on 5 July 2020. Retrieved 3 July 2020.
  45. ^ a b c 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.
  46. ^ a b c d e f 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): 41–47. doi:10.1097/FPC.0000000000000100. PMC 4261059. PMID 25370453.
  47. ^ Soeiro MN, Werbovetz K, Boykin DW, Wilson WD, Wang MZ, Hemphill A (July 2013). "Novel amidines and analogues as promising agents against intracellular parasites: a systematic review". Parasitology. 140 (8): 929–51. doi:10.1017/S0031182013000292. PMC 3815587. PMID 23561006.
  48. ^ Ortiz de Montellano PR (February 2013). "Cytochrome P450-activated prodrugs". Future Med Chem. 5 (2): 213–28. doi:10.4155/fmc.12.197. PMC 3697796. PMID 23360144.
  49. ^ 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): 4118–4126. doi:10.1074/jbc.275.6.4118. PMID 10660572. S2CID 41956184.
  50. ^ a b c d Yokomizo T, Izumi T, Shimizu T (January 2001). "Leukotriene B4: metabolism and signal transduction". Archives of Biochemistry and Biophysics. 385 (2): 231–241. doi:10.1006/abbi.2000.2168. PMID 11368003.
  51. ^ Wang T, Fu X, Chen Q, Patra JK, Wang D, Wang Z, Gai Z (July 2019). "Arachidonic Acid Metabolism and Kidney Inflammation". International Journal of Molecular Sciences. 20 (15): 3683. doi:10.3390/ijms20153683. PMC 6695795. PMID 31357612.
  52. ^ Ohnishi H, Miyahara N, Gelfand EW (December 2008). "The role of leukotriene B(4) in allergic diseases". Allergology International. 57 (4): 291–298. doi:10.2332/allergolint.08-RAI-0019. PMID 18797182.
  53. ^ 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.
  54. ^ a b 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.
  55. ^ a b c d e Hardwick JP (June 2008). "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases". Biochemical Pharmacology. 75 (12): 2263–2275. doi:10.1016/j.bcp.2008.03.004. PMID 18433732.
  56. ^ Crooks SW, Stockley RA (February 1998). "Leukotriene B4". The International Journal of Biochemistry & Cell Biology. 30 (2): 173–178. doi:10.1016/s1357-2725(97)00123-4. PMID 9608670. S2CID 45983006.
  57. ^ Le Bel M, Brunet A, Gosselin J (2014). "Leukotriene B4, an endogenous stimulator of the innate immune response against pathogens". Journal of Innate Immunity. 6 (2): 159–168. doi:10.1159/000353694. PMC 6741447. PMID 23988515.
  58. ^ Das UN (December 2021). "Essential Fatty Acids and Their Metabolites in the Pathobiology of Inflammation and Its Resolution". Biomolecules. 11 (12): 1873. doi:10.3390/biom11121873. PMC 8699107. PMID 34944517.
  59. ^ He R, Chen Y, Cai Q (August 2020). "The role of the LTB4-BLT1 axis in health and disease". Pharmacological Research. 158: 104857. doi:10.1016/j.phrs.2020.104857. PMID 32439596. S2CID 218834028.
  60. ^ 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.
  61. ^ a b c 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): 201–205. doi:10.1006/abbi.1998.0724. PMID 9675028.
  62. ^ a b Johnson AL, Edson KZ, Totah RA, Rettie AE (2015). "Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer". Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer. Adv Pharmacol. Vol. 74. Academic Press. pp. 223–62. doi:10.1016/bs.apha.2015.05.002. ISBN 978-0-12-803119-3. PMC 4667791. PMID 26233909.
  63. ^ Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, Amre DK (April 2014). "Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease". Gastroenterology. 146 (4): 929–931. doi:10.1053/j.gastro.2013.12.034. PMID 24406470. Archived from the original on 3 July 2020. Retrieved 3 July 2020.
  64. ^ Costea I, Mack DR, Israel D, Morgan K, Krupoves A, Seidman E, et al. (December 2010). "Genes involved in the metabolism of poly-unsaturated fatty-acids (PUFA) and risk for Crohn's disease in children & young adults". PLOS ONE. 5 (12): e15672. Bibcode:2010PLoSO...515672C. doi:10.1371/journal.pone.0015672. PMC 3004960. PMID 21187935.
  65. ^ Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C (November 2006). "A functional candidate screen for coeliac disease genes". European Journal of Human Genetics. 14 (11): 1215–1222. doi:10.1038/sj.ejhg.5201687. PMID 16835590.
  66. ^ a b Dhar M, Sepkovic DW, Hirani V, Magnusson RP, Lasker JM (March 2008). "Omega oxidation of 3-hydroxy fatty acids by the human CYP4F gene subfamily enzyme CYP4F11". Journal of Lipid Research. 49 (3): 612–624. doi:10.1194/jlr.M700450-JLR200. PMID 18065749. S2CID 28835933.
  67. ^ a b Le Quéré V, Plée-Gautier E, Potin P, Madec S, Salaün JP (August 2004). "Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides". Journal of Lipid Research. 45 (8): 1446–1458. doi:10.1194/jlr.M300463-JLR200. PMID 15145985. S2CID 6065789.
  68. ^ Sanders RJ, Ofman R, Duran M, Kemp S, Wanders RJ (May 2006). "Omega-oxidation of very long-chain fatty acids in human liver microsomes. Implications for X-linked adrenoleukodystrophy". The Journal of Biological Chemistry. 281 (19): 13180–13187. doi:10.1074/jbc.M513481200. PMID 16547005. S2CID 26142051.
  69. ^ Sanders RJ, Ofman R, Dacremont G, Wanders RJ, Kemp S (June 2008). "Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids". FASEB Journal. 22 (6): 2064–2071. doi:10.1096/fj.07-099150. hdl:1854/LU-745741. PMID 18182499. S2CID 36659127. Archived from the original on 3 July 2020. Retrieved 3 July 2020.
  70. ^ Stipanuk MH, Caudill MA (2018). Biochemical, Physiological, and Molecular Aspects of Human Nutrition - E-Book (4th ed.). Elsevier Health Sciences. ISBN 978-0-323-40213-2. Archived from the original on 15 July 2020. Retrieved 4 July 2020.
  71. ^ Böhm V (2018). Vitamin E. MDPI - Multidisciplinary Digital Publishing Institute. p. 60. doi:10.3390/books978-3-03842-906-7. ISBN 978-3-03842-906-7. Archived from the original on 5 July 2020. Retrieved 4 July 2020.
  72. ^ Snyder F (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.
  73. ^ Numa S, ed. (January 1984). Fatty Acid Metabolism and its Regulation. Elsevier. p. 132. ISBN 0-444-80528-1. Archived from the original on 7 July 2021. Retrieved 12 July 2020.
  74. ^ Parker RS, Sontag TJ, Swanson JE, McCormick CC (December 2004). "Discovery, characterization, and significance of the cytochrome P450 omega-hydroxylase pathway of vitamin E catabolism". Annals of the New York Academy of Sciences. 1031 (1): 13–21. Bibcode:2004NYASA1031...13P. doi:10.1196/annals.1331.002. PMID 15753130. S2CID 33584273.
  75. ^ a b 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): 1901–1906. doi:10.3945/jn.110.128579. PMC 2955872. PMID 20861217.
  76. ^ a b Sontag TJ, Parker RS (July 2002). "Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status". The Journal of Biological Chemistry. 277 (28): 25290–25296. doi:10.1074/jbc.M201466200. PMID 11997390. S2CID 743292.
  77. ^ a b c d e 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): 746–756. doi:10.1038/clpt.2012.184. PMC 3731755. PMID 23132553.
  78. ^ Kurosu M, Begari E (March 2010). "Vitamin K2 in electron transport system: are enzymes involved in vitamin K2 biosynthesis promising drug targets?". Molecules. 15 (3): 1531–53. doi:10.3390/molecules15031531. PMC 6257245. PMID 20335999.
  79. ^ McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE (June 2009). "CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant". Molecular Pharmacology. 75 (6): 1337–1346. doi:10.1124/mol.109.054833. PMC 2684883. PMID 19297519.
  80. ^ Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC (July 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.
  81. ^ Froogh G, Garcia V, Laniado Schwartzman M (2022). "The CYP/20-HETE/GPR75 axis in hypertension". New Targets for the Treatment of Hypertension and Associated Diseases. Adv Pharmacol. Vol. 94. Academic Press. pp. 1–25. doi:10.1016/bs.apha.2022.02.003. ISBN 978-0-323-91087-3. PMC 10123763. PMID 35659370.
  82. ^ Gonzalez-Fernandez E, Liu Y, Auchus AP, Fan F, Roman RJ (August 2021). "Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE". Clinical Science. 135 (15): 1929–1944. doi:10.1042/CS20201033. PMC 8783562. PMID 34374423.
  83. ^ a b Shekhar S, Varghese K, Li M, Fan L, Booz GW, Roman RJ, Fan F (September 2019). "Conflicting Roles of 20-HETE in Hypertension and Stroke". International Journal of Molecular Sciences. 20 (18): 4500. doi:10.3390/ijms20184500. PMC 6770042. PMID 31514409.
  84. ^ Fava C, Bonafini S (November 2018). "Eicosanoids via CYP450 and cardiovascular disease: Hints from genetic and nutrition studies". Prostaglandins & Other Lipid Mediators. 139: 41–47. doi:10.1016/j.prostaglandins.2018.10.001. PMID 30296490. S2CID 52943912.
  85. ^ Wang MZ, Wu JQ, Bridges AS, Zeldin DC, Kornbluth S, Tidwell RR, et al. (November 2007). "Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine". Drug Metabolism and Disposition. 35 (11): 2067–2075. doi:10.1124/dmd.107.016428. PMC 2364724. PMID 17709372.
  86. ^ Wang MZ, Saulter JY, Usuki E, Cheung YL, Hall M, Bridges AS, et al. (December 2006). "CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime]". Drug Metabolism and Disposition. 34 (12): 1985–1994. doi:10.1124/dmd.106.010587. PMC 2077835. PMID 16997912.
  87. ^ a b c David OJ, Kovarik JM, Schmouder RL (January 2012). "Clinical pharmacokinetics of fingolimod". Clin Pharmacokinet. 51 (1): 15–28. doi:10.2165/11596550-000000000-00000. PMID 22149256. S2CID 207301139.
  88. ^ Fahmi AM, Elewa H, El Jilany I (June 2022). "Warfarin dosing strategies evolution and its progress in the era of precision medicine, a narrative review". International Journal of Clinical Pharmacy. 44 (3): 599–607. doi:10.1007/s11096-022-01386-8. PMC 9200678. PMID 35247148.
  89. ^ a b c d Cross B, Turner RM, Zhang JE, Pirmohamed M (March 2024). "Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?". Pharmacogenomics J. 24 (2): 7. doi:10.1038/s41397-024-00329-y. PMC 10914631. PMID 38443337.
  90. ^ "PharmGKB". Archived from the original on 26 November 2023. Retrieved 26 November 2023.
  91. ^ Public Domain This article incorporates public domain material from "Rs2108622 RefSNP Report - DBSNP - NCBI". The Single Nucleotide Polymorphism database (dbSNP). National Center for Biotechnology Information.
  92. ^ Public Domain This article incorporates public domain material from "Rs2108622 RefSNP Report - DBSNP - NCBI - Allele frequency". The Single Nucleotide Polymorphism database (dbSNP). National Center for Biotechnology Information.
  93. ^ Major JM, Yu K, Wheeler W, Zhang H, Cornelis MC, Wright ME, et al. (October 2011). "Genome-wide association study identifies common variants associated with circulating vitamin E levels". Human Molecular Genetics. 20 (19): 3876–3883. doi:10.1093/hmg/ddr296. PMC 3168288. PMID 21729881.
  94. ^ Geng H, Li B, Wang Y, Wang L (May 2019). "Association Between the CYP4F2 Gene rs1558139 and rs2108622 Polymorphisms and Hypertension: A Meta-Analysis". Genetic Testing and Molecular Biomarkers. 23 (5): 342–347. doi:10.1089/gtmb.2018.0202. PMID 30932691. S2CID 89620562.
  95. ^ Luo XH, Li GR, Li HY (November 2015). "Association of the CYP4F2 rs2108622 genetic polymorphism with hypertension: a meta-analysis". Genetics and Molecular Research. 14 (4): 15133–15139. doi:10.4238/2015.November.25.1. PMID 26634476.
  96. ^ "PharmGKB". Archived from the original on 26 November 2023. Retrieved 26 November 2023.
  97. ^ Michaels S, Wang MZ (August 2014). "The revised human liver cytochrome P450 "Pie": absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics". Drug Metab Dispos. 42 (8): 1241–51. doi:10.1124/dmd.114.058040. PMC 4109210. PMID 24816681.
  98. ^ Gómez-Valenzuela F, Escobar E, Pérez-Tomás R, Montecinos VP (2021). "The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition". Front Oncol. 11: 686792. doi:10.3389/fonc.2021.686792. PMC 8222670. PMID 34178680.
  99. ^ Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA (2014). "Chronic inflammation and cytokines in the tumor microenvironment". J Immunol Res. 2014: 149185. doi:10.1155/2014/149185. PMC 4036716. PMID 24901008.
  100. ^ Swanson HI, Njar VC, Yu Z, Castro DJ, Gonzalez FJ, Williams DE, Huang Y, Kong AN, Doloff JC, Ma J, Waxman DJ, Scott EE (April 2010). "Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy". Drug Metab Dispos. 38 (4): 539–44. doi:10.1124/dmd.109.031351. PMC 2845935. PMID 20233842.
  101. ^ van Eijk M, Boosman RJ, Schinkel AH, Huitema AD, Beijnen JH (September 2019). "Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: relevance for resistance to taxanes". Cancer Chemother Pharmacol. 84 (3): 487–499. doi:10.1007/s00280-019-03905-3. PMC 6682574. PMID 31309254.
  102. ^ Dai E, Zhu Z, Wahed S, Qu Z, Storkus WJ, Guo ZS (December 2021). "Epigenetic modulation of antitumor immunity for improved cancer immunotherapy". Mol Cancer. 20 (1): 171. doi:10.1186/s12943-021-01464-x. PMC 8691037. PMID 34930302.
  103. ^ a b Heng YM, Kuo CS, Jones PS, Savory R, Schulz RM, Tomlinson SR, et al. (August 1997). "A novel murine P-450 gene, Cyp4a14, is part of a cluster of Cyp4a and Cyp4b, but not of CYP4F, genes in mouse and humans". The Biochemical Journal. 325 (Pt 3): 741–749. doi:10.1042/bj3250741. PMC 1218619. PMID 9271096.
  104. ^ Kikuta Y, Miyauchi Y, Kusunose E, Kusunose M (September 1999). "Expression and molecular cloning of human liver leukotriene B4 omega-hydroxylase (CYP4F2) gene". DNA and Cell Biology. 18 (9): 723–730. doi:10.1089/104454999315006. PMID 10492403.
Retrieved from "https://en.wikipedia.org/w/index.php?title=CYP4F2&oldid=1239353459"