CYP2E1

Last updated
CYP2E1
Protein CYP2E1 PDB 3E4E.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CYP2E1 , CPE1, CYP2E, P450-J, P450C2E, cytochrome P450 family 2 subfamily E member 1
External IDs OMIM: 124040 MGI: 88607 HomoloGene: 68089 GeneCards: CYP2E1
EC number 1.14.13.n7
Orthologs
SpeciesHumanMouse
Entrez

1571

13106

Ensembl

ENSG00000130649

ENSMUSG00000025479

UniProt

P05181

Q05421

RefSeq (mRNA)

NM_000773

NM_021282

RefSeq (protein)

NP_000764

NP_067257

Location (UCSC) Chr 10: 133.52 – 133.56 Mb Chr 7: 140.34 – 140.35 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cytochrome P450 2E1 (abbreviated CYP2E1, EC 1.14.13.n7) 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. [5]

Contents

While CYP2E1 itself carries out a relatively low number of these reactions (~4% of known P450-mediated drug oxidations), it and related enzymes CYP1A2 and CYP3A4 are responsible for the breakdown of many toxic environmental chemicals and carcinogens that enter the body, in addition to basic metabolic reactions such as fatty acid oxidations. [6]

CYP2E1 protein localizes to the endoplasmic reticulum and is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer. [7]

Function

CYP2E1 is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome P450 mRNA [8] and 7% of the hepatic cytochrome P450 protein. [9] The liver is therefore where most drugs undergo deactivation by CYP2E1, either directly or by facilitated excretion from the body.

CYP2E1 enzyme metabolizes mostly small, polar molecules, including toxic laboratory chemicals such as dimethylformamide, aniline, and halogenated hydrocarbons (see table below). While these oxidations are often of benefit to the body, certain carcinogens and toxins are bioactivated by CYP2E1, implicating the enzyme in the onset of hepatotoxicity caused by certain classes of drugs (see disease relevance section below).

CYP2E1 also plays a role in several important metabolic reactions, including the conversion of ethanol to acetaldehyde and to acetate in humans, [10] where it works alongside alcohol dehydrogenase and aldehyde dehydrogenase. In the conversion sequence of acetyl-CoA to glucose, CYP2E1 transforms acetone via hydroxyacetone (acetol) into propylene glycol and methylglyoxal, the precursors of pyruvate, acetate and lactate. [11] [12] [13]

CYP2E1 also carries out the metabolism of endogenous fatty acids such as the ω-1 hydroxylation of fatty acids such as arachidonic acid, involving it in important signaling pathways that may link it to diabetes and obesity. [14] Thus, it acts as a monooxygenase to metabolize arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid). However, it also acts as an epoxygenase activity to metabolize docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenoic acid and 17S,18R-eicosatetraenoic acid isomers (termed 17,18-EEQ). [15] 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles, elevates blood pressure, promotes inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated (see 20-Hydroxyeicosatetraenoic acid). The EDP (see Epoxydocosapentaenoic acid) and EEQ (see epoxyeicosatetraenoic acid) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines. [16] [17] [18] [19] It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids. [16] [19] [20] EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally. CYP2E1 is not regarded as being a major contributor to forming the cited epoxides [19] but could act locally in certain tissues to do so.

Substrates

Following is a table of selected substrates of CYP2E1. Where classes of agents are listed, there may be exceptions within the class.

Selected substrates of CYP2E1
Substrates

Structure

CYP2E1 exhibits structural motifs common to other human membrane-bound cytochrome P450 enzymes, and is composed of 12 major α-helices and 4 β-sheets with short intervening helices interspersed between the two. [14] Like other enzymes of this class, the active site of CYP2E1 contains an iron atom bound by a heme center which mediates the electron transfer steps necessary to carry out oxidation of its substrates. The active site of CYP2E1 is the smallest observed in human P450 enzymes, with its small capacity attributed in part to the introduction of an isoleucine at position 115. The side-chain of this residue protrudes out above the heme center, restricting active site volume compared to related enzymes that have less bulky residues at this position. [14] T303, which also protrudes into the active site, is particularly important for substrate positioning above the reactive iron center and is hence highly conserved by many cytochrome P450 enzymes. [14] Its hydroxyl group is well-positioned to donate a hydrogen bond to potential acceptors on the substrate, and its methyl group has also been implicated in the positioning of fatty acids within the active site. [25] , [26] A number of residues proximal to the active site including L368 help make up a constricted, hydrophobic access channel which may also be important for determining the enzyme's specificity towards small molecules and ω-1 hydroxylation of fatty acids. [14]

Selected residues in the active site of CYP2E1. Created using 3E4E (bound to inhibitor 4-methyl pyrazole) CYP2E1 Active site.png
Selected residues in the active site of CYP2E1. Created using 3E4E (bound to inhibitor 4-methyl pyrazole)

.

Regulation

Genetic regulation

In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene. [27] The enzyme has been identified in fetal liver, where it is posited to be the predominant ethanol-metabolizing enzyme, and may be connected to ethanol-mediated teratogenesis. [28] In rats, within one day of birth the hepatic CYP2E1 gene is activated transcriptionally.

CYP2E1 expression is easily inducible, and can occur in the presence of a number of its substrates, including ethanol, [22] isoniazid, [22] tobacco, [29] isopropanol, [6] benzene, [6] toluene, [6] and acetone. [6] For ethanol specifically, it seems that there exist two stages of induction, a post-translational mechanism for increased protein stability at low levels of ethanol and an additional transcriptional induction at high levels of ethanol. [30]

Chemical regulation

CYP2E1 is inhibited by a variety of small molecules, many of which act competitively. Two such inhibitors, indazole and 4-methylpyrazole, coordinate with the active site's iron atom and were crystallized with recombinant human CYP2E1 in 2008 to give the first true crystal structures of the enzyme. [14] Other inhibitors include diethyldithiocarbamate [21] (in cancer), and disulfiram [22] (in alcoholism).

Disease relevance

CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body. [8] [9] In doing so, CYP2E1 bioactivates a variety of common anesthetics, including paracetamol (acetaminophen), halothane, enflurane, and isoflurane. [6] The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride from halothane [31] or NAPQI from paracetamol (acetaminophen) and is a major reason for their observed hepatotoxicity in patients.

CYP2E1 and other cytochrome P450 enzymes can inadvertently produce reactive oxygen species (ROS) in their active site when catalysis is not coordinated correctly, resulting in potential lipid peroxidation as well as protein and DNA oxidation. [14] CYP2E1 is particularly susceptible to this phenomenon compared to other P450 enzymes, suggesting that its expression levels may be important for negative physiological effects observed in a number of disease states. [14]

CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption, [32] diabetes, [33] fasting, [34] and obesity. [35] It appears that cellular levels of the enzyme may be controlled by the molecular chaperone HSP90, which upon association with CYP2E1 allows for transport to the proteasome and subsequent degradation. Ethanol and other substrates may disrupt this association, leading to the higher expression levels observed in their presence. [36] The increased expression of CYP2E1 accompanying these health conditions may therefore contribute to their pathogenesis by increasing the rate of production of ROS in the body. [14]

According to a 1995 publication by Y Hu et al., a study in rats revealed a 8- to 9-fold elevation of CYP2E1 with fasting alone, compared to a 20-fold increase in enzyme level accompanied by a 16-fold increase in total catalytic capacity in rats who were both fasted and given large quantities of ethanol for 3 consecutive days. Starvation appears to upregulate CYP2E1 mRNA production in liver cells while alcohol seems to stabilize the enzyme itself post-translation and thus protect it from degradation by normal cellular proteolytic processes, giving the two an independent synergistic effect.

Applications

Trees have been genetically engineered to overexpress rabbit CYP2E1 enzyme. These transgenic trees have been used to remove pollutants from groundwater, a process known as phytoremediation. [37]

See also

Related Research Articles

<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. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.

<span class="mw-page-title-main">CYP3A4</span> Enzyme which breaks down foreign organic molecules

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

<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 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.

<span class="mw-page-title-main">CYP2C19</span> Mammalian protein found in humans

Cytochrome P450 2C19 is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.

<span class="mw-page-title-main">CYP2C8</span> Gene-coded protein involved in metabolism of xenobiotics

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.

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">CYP2J2</span> Gene of the species Homo sapiens

Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.

<span class="mw-page-title-main">CYP2C18</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.

<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">CYP4F2</span> Protein-coding gene in the species Homo sapiens

Leukotriene-B(4) omega-hydroxylase 1 is an enzyme protein involved in the metabolism of various endogenous substrates and xenobiotics. The most notable substrate of the enzyme is leukotriene B4, a potent mediator of inflammation. The CYP4F2 gene encodes the enzyme in humans.

<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

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">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">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acid's (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, Vicinal (chemistry) dihydroxy fatty acids by ubiquitous cellular Soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

<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.

References

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