CYP4F2

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Cytochrome P450 4F2
CYP4F2 AF AFP78329F1.png
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.
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
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PMC articles
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NCBI proteins
CYP4F2
Identifiers
Aliases CYP4F2 , CPF2, cytochrome P450 family 4 subfamily F member 2
External IDs OMIM: 604426 MGI: 1919304 HomoloGene: 128623 GeneCards: CYP4F2
EC number 1.14.14.94
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 Mb Chr 8: 72.74 – 72.76 Mb
PubMed search [4] [5]
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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.

Contents

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

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:

Protein

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

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

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

The cytochrome P450 superfamily

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

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

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

Biosynthesis of leukotriene B4 from arachidonic acid

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

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

Hydroxylation of Leukotriene B4 catalyzed by CYP4F2 Leukotriene B4 hydroxylation traced.svg
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

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

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

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

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

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

Genetic variants

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

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

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

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]

Related Research Articles

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown, steroid hormone synthesis, drug metabolism, and the biosynthesis of defensive compounds, fatty acids, and hormones. CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. In almost all of the transformations that they catalyze, P450's affect hydroxylation.

<span class="mw-page-title-main">CYP2E1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, soluble epoxide hydrolase (sEH), also termed epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them or of nearby cells. The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as heart attacks and brain strokes not only by their anti-hypertension action but possibly also by their anti-inflammatory effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon. The process is normally a minor catabolic pathway for medium-chain fatty acids, but becomes more important when β oxidation is defective.

<span class="mw-page-title-main">CYP1A1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.

<span class="mw-page-title-main">CYP4A11</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.

<span class="mw-page-title-main">CYP4F8</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.

<span class="mw-page-title-main">CYP4F12</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12 gene.

<span class="mw-page-title-main">CYP4F3</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F3, also leukotriene-B(4) omega-hydroxylase 2, is an enzyme that in humans is encoded by the CYP4F3 gene. 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.

Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 enzymes that metabolize polyunsaturated fatty acids to epoxide products that have a range of biological activities. The most thoroughly studied substrate of the CYP epoxylgenases is arachidonic acid. This polyunsaturated fatty acid is metabolized by cyclooxygenases to various prostaglandin, thromboxane, and prostacyclin metabolites in what has been termed the first pathway of eicosanoid production; it is also metabolized by various lipoxygenases to hydroxyeicosatetraenoic acids and leukotrienes in what has been termed the second pathway of eicosanoid production. The metabolism of arachidonic acid to epoxyeicosatrienoic acids by the CYP epoxygenases has been termed the third pathway of eicosanoid metabolism. Like the first two pathways of eicosanoid production, this third pathway acts as a signaling pathway wherein a set of enzymes metabolize arachidonic acid to a set of products that act as secondary signals to work in activating their parent or nearby cells and thereby orchestrate functional responses. However, none of these three pathways is limited to metabolizing arachidonic acid to eicosanoids. Rather, they also metabolize other polyunsaturated fatty acids to products that are structurally analogous to the eicosanoids but often have different bioactivity profiles. This is particularly true for the CYP epoxygenases which in general act on a broader range of polyunsaturated fatty acids to form a broader range of metabolites than the first and second pathways of eicosanoid production. Furthermore, the latter pathways form metabolites many of which act on cells by binding with and thereby activating specific and well-characterized receptor proteins; no such receptors have been fully characterized for the epoxide metabolites. Finally, there are relatively few metabolite-forming lipoxygenases and cyclooxygenases in the first and second pathways and these oxygenase enzymes share similarity between humans and other mammalian animal models. The third pathway consists of a large number of metabolite-forming CYP epoxygenases and the human epoxygenases have important differences from those of animal models. Partly because of these differences, it has been difficult to define clear roles for the epoxygenase-epoxide pathways in human physiology and pathology.

<span class="mw-page-title-main">CYP4F11</span> Protein-coding gene in the species Homo sapiens

CYP4F11 is a protein that in humans is encoded by the CYP4F11 gene. 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 gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F2, is approximately 16 kb away. Alternatively spliced transcript variants encoding the same protein have been found for this gene.

<span class="mw-page-title-main">CYP4A22</span> Protein-coding gene in the species Homo sapiens

CYP4A22 also known as fatty acid omega-hydroxylase is a protein which in humans is encoded by the CYP4A22 gene.

<span class="mw-page-title-main">CYP2U1</span> Protein-coding gene in the species Homo sapiens

CYP2U1 is a protein that in humans is encoded by the CYP2U1 gene

<span class="mw-page-title-main">12-Hydroxyheptadecatrienoic acid</span> Chemical compound

12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was discovered and structurally defined in 1973 by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg, as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.

<span class="mw-page-title-main">20-Hydroxyeicosatetraenoic acid</span> Chemical compound

20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regulation of vascular tone, blood flow to specific organs, sodium and fluid transport in the kidney, and vascular pathway remodeling. These vascular and kidney effects of 20-HETE have been shown to be responsible for regulating blood pressure and blood flow to specific organs in rodents; genetic and preclinical studies suggest that 20-HETE may similarly regulate blood pressure and contribute to the development of stroke and heart attacks. Additionally the loss of its production appears to be one cause of the human neurological disease, Hereditary spastic paraplegia. Preclinical studies also suggest that the overproduction of 20-HETE may contribute to the progression of certain human cancers, particularly those of the breast.

<span class="mw-page-title-main">Epoxyeicosatetraenoic acid</span> Chemical compound

Epoxyeicosatetraenoic acids are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenases can metabolize EPA to as many as 10 epoxides that differ in the site and/or stereoisomer of the epoxide formed; however, the formed EEQs, while differing in potency, often have similar bioactivities and are commonly considered together.

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

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