39-512: 2HI4 1544 13077 ENSG00000140505 ENSMUSG00000032310 P05177 P00186 NM_000761 NM_009993 NP_000752 NP_034123 Cytochrome P450 1A2 (abbreviated CYP1A2 ), 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 . CYP1A2
78-495: A "reverse type I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type II difference spectrum, with a maximum at 430 nm and a minimum at 390 nm (see inset graph in figure). If no reducing equivalents are available, this complex may remain stable, allowing the degree of binding to be determined from absorbance measurements in vitro C: If carbon monoxide (CO) binds to reduced P450,
117-517: 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. It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of
156-449: A different sEH inhibitor, GSK2256294, developed for chronic obstructive pulmonary disease by GlaxoSmithKline has entered the pre-recruiting phase of a phase I clinical trial for obese male smokers. EicOsis designs and applies sEH inhibitors towards treating chronic pain in humans, companion animals and horses. The inhibitor EC 1728 has been shown to successfully treat equine laminitis and alleviate inflammatory pain in dogs and cats and
195-451: A heme-iron center. The iron is tethered to the protein via a cysteine thiolate ligand . This cysteine and several flanking residues are highly conserved in known P450s, and have the formal PROSITE signature consensus pattern [FW] - [SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD]. In general, the P450 catalytic cycle proceeds as follows: Mechanistic details, including
234-492: A key intermediate in the synthesis of cholesterol. EETs are lipid signaling molecules that function in an autocrine and paracrine manner. They are produced when arachidonic acid is metabolized by cytochrome p450s (CYPs). These enzymes epoxidize the double bonds in arachidonic acid to form four regioisomers. Arachidonic acid is also the precursor of the prostaglandins and the leukotrienes, which are produced by cyclooxygenases and lipoxygenases, respectively. These lipids play
273-633: A major contributor to forming the aforementioned epoxides but could act locally in certain tissues to do so. The authoritative list of star allele nomenclature for CYP1A2 along with activity scores is kept by PharmVar. Expression of CYP1A2 appears to be induced by various dietary constituents. Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2. Lower activity of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such as cumin and turmeric , ingredients known to inhibit
312-754: A role in asthma, pain, and inflammation and are the targets of several pharmaceuticals. The EET receptor or receptors have not been identified, but several tools for the study of EET biology have been developed, these include small molecule sEH inhibitors, EET mimics and sEH genetic models. Through the use of these tools, as well as the EETs themselves, the EETs have been found to have anti-inflammatory and vasoactive properties. Several disease models have been used, including Ang-II induced hypertension and surgical models of brain and heart ischemia. In vitro models such as isolated coronary rings and platelet aggregation assays have also been employed. The proposed role of sEH in
351-524: Is a bifunctional enzyme that in humans is encoded by the EPHX2 gene . sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes , binds to specific epoxides and converts them to the corresponding diols . A different region of this protein also has lipid-phosphate phosphatase activity. Mutations in the EPHX2 gene have been associated with familial hypercholesterolemia . While most highly expressed in
390-432: Is 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. CYP1A2 localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate
429-419: 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. The EDP ( epoxydocosapentaenoic acid ) and EEQ ( epoxyeicosatetraenoic acid ) metabolites have
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#1732775797316468-453: Is currently undergoing clinical trials in horses. The sEH inhibitor EC 5026 has been selected as the therapeutic for diabetic neuropathy and recently entered Phase 1 clinical trials. Thus, interest continues in sEH as a therapeutic target. Another drug described as a small-molecule thrombolytic with multiple mechanisms of action, SMTP-7 , has been found to act as a sEH inhibitor, but is still at early experimental stages. One indication of
507-430: Is still unknown. Through metabolism of EETs and other lipid mediators, sEH plays a role in several diseases, including hypertension , cardiac hypertrophy , arteriosclerosis , brain and heart ischemia / reperfusion injury , cancer and pain. Because of its possible role in cardiovascular and other diseases, sEH is being pursued as a pharmacological target, and potent small molecule inhibitors are available. Because of
546-515: Is the gene that encodes the enzyme CYP2E1 —one of the enzymes involved in paracetamol (acetaminophen) metabolism. The CYP nomenclature is the official naming convention, although occasionally CYP450 or CYP 450 is used synonymously. These names should never be used as according to the nomenclature convention (as they denote a P450 in family number 450). However, some gene or enzyme names for P450s are also referred to by historical names (e.g. P450 BM3 for CYP102A1) or functional names, denoting
585-1093: Is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include caffeine , aflatoxin B1, and paracetamol (acetaminophen). The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. CYP1A2 also metabolizes polyunsaturated fatty acids into signaling molecules that have physiological as well as pathological activities. It has monoxygenase activity for certain of these fatty acids in that it metabolizes arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid ) but also has epoxygenase activity in that it metabolizes docosahexaenoic acid to epoxides , primarily 19 R ,20 S -epoxyeicosapentaenoic acid and 19 S ,20 R -epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes eicosapentaenoic acid to epoxides, primarily 17 R ,18 S - eicosatetraenoic acid and 17 S ,18 R -eicosatetraenoic acid isomers (termed 17,18-EEQ). 19-HETE
624-527: The C-terminal epoxide hydrolase activity ( soluble epoxide hydrolase : EC 3.3.2.10) and the N-terminal phosphatase activity ( lipid-phosphate phosphatase : EC 3.1.3.76). sEH converts epoxides, or three membered cyclic ethers, to their corresponding diols through the addition of a molecule of water. The resulting diols are more water-soluble than the parent epoxides, and so are more readily excreted by
663-786: The United States National Library of Medicine , which is in the public domain . Cytochrome P450 Cytochromes P450 ( P450s or CYPs ) are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases . However, they are not omnipresent; for example, they have not been found in Escherichia coli . In mammals, these enzymes oxidize steroids , fatty acids , xenobiotics , and participate in many biosyntheses. By hydroxylation, CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted. P450s are, in general,
702-852: The Wayback Machine ) and allele names ( CYP Allele Nomenclature Committee ). Based on the nature of the electron transfer proteins, P450s can be classified into several groups: The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH), while the other oxygen atom is reduced to water: Many hydroxylation reactions (insertion of hydroxyl groups) use CYP enzymes, but many other hydroxylases exist. Alpha-ketoglutarate-dependent hydroxylases also rely on an Fe=O intermediate but lack hemes. Methane monooxygenase, which converts methane to methanol, are non-heme iron-and iron-copper-based enzymes. The active site of cytochrome P450 contains
741-631: The arginine in position 287 in the most frequent allele to glutamine , while K55R changes the lysine in position 55 to an arginine. R287Q was associated with coronary artery calcification in African American population participating in the CARDIA study. The K55R allele is associated with the risk of developing coronary heart disease in Caucasians participating in the ARIC study, where it
780-407: The iron (and eventually molecular oxygen ). Genes encoding P450 enzymes, and the enzymes themselves, are designated with the root symbol CYP for the superfamily , followed by a number indicating the gene family , a capital letter indicating the subfamily, and another numeral for the individual gene. The convention is to italicize the name when referring to the gene. For example, CYP2E1
819-417: 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. 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. CYP1A2 is not regarded as being
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#1732775797316858-480: The oxygen rebound mechanism , have been investigated with synthetic analogues, consisting of iron oxo heme complexes. Binding of substrate is reflected in the spectral properties of the enzyme, with an increase in absorbance at 390 nm and a decrease at 420 nm. This can be measured by difference spectroscopies and is referred to as the "type I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties,
897-649: The biologically active epoxyalcohol metabolites of arachidnoic acid, hepoxilin A3 (8-hydroxy-11 S ,12 S epoxy-(5 Z ,8 Z ,14 Z )-eicosatrienoic acid) to trioxilin A3 (8,11,12-trihydroxy-(5 Z ,9 E ,14 Z )-eicosatrienoic acid) and hepoxilin B3 (10-hydroxy-11 S ,12 S epoxy-(5 Z ,9 E ,14 Z )-eicosatrienoic acid) to trioxlin B3 (10,11,12-trihydroxy-(5 Z ,9 E ,14 Z )-eicosatrienoic acid. These trihydroxy products are generally considered to be inactive and
936-670: The catalytic activity and the name of the compound used as substrate. Examples include CYP5A1 , thromboxane A 2 synthase, abbreviated to TBXAS1 ( T hrom B o X ane A 2 S ynthase 1 ), and CYP51A1 , lanosterol 14-α-demethylase, sometimes unofficially abbreviated to LDM according to its substrate ( L anosterol) and activity ( D e M ethylation). The current nomenclature guidelines suggest that members of new CYP families share at least 40% amino-acid identity, while members of subfamilies must share at least 55% amino-acid identity. Nomenclature committees assign and track both base gene names ( Cytochrome P450 Homepage Archived 2010-06-27 at
975-1525: The catalytic cycle is interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450 nm. However, the interruptive and inhibitory effects of CO varies upon different CYPs such that the CYP3A family is relatively less affected. Soluble epoxide hydrolase 1S8O , 1VJ5 , 1ZD2 , 1ZD3 , 1ZD4 , 1ZD5 , 3ANS , 3ANT , 3I1Y , 3I28 , 3KOO , 3OTQ , 3PDC , 3WK4 , 3WK5 , 3WK6 , 3WK7 , 3WK8 , 3WK9 , 3WKA , 3WKB , 3WKC , 3WKD , 3WKE , 4C4X , 4C4Y , 4C4Z , 4HAI , 4J03 , 4JNC , 4OCZ , 4OD0 , 4X6X , 4X6Y , 4Y2J , 4Y2P , 4Y2Q , 4Y2R , 4Y2S , 4Y2T , 4Y2U , 4Y2V , 4Y2X , 4Y2Y , 5AHX , 5AI0 , 5AI4 , 5AI5 , 5AI6 , 5AI8 , 5AI9 , 5AIA , 5AIB , 5AIC , 5AK3 , 5AK4 , 5AK5 , 5AK6 , 5AKE , 5AKG , 5AKH , 5AKI , 5AKJ , 5AKK , 5AKL , 5AKX , 5AKY , 5AKZ , 5ALD , 5ALE , 5ALF , 5ALG , 5ALH , 5ALI , 5ALJ , 5ALK , 5ALL , 5ALM , 5ALN , 5ALO , 5ALP , 5ALQ , 5ALR , 5ALS , 5ALT , 5ALU , 5ALV , 5ALW , 5ALX , 5ALY , 5ALZ , 5AM0 , 5AM1 , 5AM2 , 5AM3 , 5AM4 , 5AM5 , 5FP0 2053 13850 ENSG00000120915 ENSMUSG00000022040 P34913 P34914 NM_001979 NM_001256482 NM_001256483 NM_001256484 NM_001271402 NM_001271403 NM_001271421 NM_007940 NP_001243411 NP_001243412 NP_001243413 NP_001970 NP_001258331 NP_001258332 NP_001258350 NP_031966 Soluble epoxide hydrolase (sEH)
1014-597: The enzyme. A single 2006 paper found CYP1A2 to be involved in the metabolization of caffeine , and the presence of alleles that make this metabolization slow have been associated with an increased risk of nonfatal myocardial infarction for those who drink a lot of coffee (4 or more cups per day). Following is a table of selected substrates , inducers and inhibitors of CYP1A2. Inhibitors of CYP1A2 can be classified by their potency , such as: Moderate Weak Unspecified potency : Moderate inducers: Unspecified potency: This article incorporates text from
1053-403: The hepoxilin hydrolase that is responsible for inactivating the epoxyalcohol metabolites of arachidonic acid, hepoxilin A3 and hepoxiin B3. The sEH was first identified in the cytosolic fraction of mouse liver through its activity on epoxide containing substrates such as juvenile hormone and lipid epoxides such as epoxystearate. The soluble EH activity was shown to be distinct from that of
1092-424: The implications to human health, sEH has been pursued as a pharmaceutical target and several sEH inhibitors have been developed in the private and public sectors. One such inhibitor, UC1153 (AR9281), was taken to a phase IIA clinal trial for treatment of hypertension by Arête Therapeutics. However, UC1153 failed the clinical trial, due in large part because of its poor pharmacokinetic properties. Since this trial,
1131-464: The liver, sEH is also expressed in other tissues including vascular endothelium , leukocytes, red blood cells, smooth muscle cells, adipocytes and the kidney proximal tubule . In the human brain, the enzyme is distributed widely, mostly in neuronal cell bodies, as well as in astrocytes and oligodendrocytes. The form of sEH in the intracellular environment is a homodimer with two distinct activities in two separate structural domains of each monomer:
1170-453: The microsomal epoxide hydrolase (mEH) previously discovered with a different substrate selectivity and cellular localization than the mEH. Studies using a lipid epoxide as a substrate detected this activity in the soluble fraction of multiple organs, though at a lesser amount than in liver and kidney. The enzyme activity was detected in rabbits, mice and rats, and humans, and it is now believed to be ubiquitous in vertebrates. The proposed enzyme
1209-427: The omega three docosahexaenoic acid ( DHA ) and eicosapentaenoic acid (EPA) epoxides. These lipid epoxides have been shown to have biological effects in vitro in which they inhibit platelet aggregation. In fact, in some assays they are more potent than the EETs. Other epoxidized lipids include the 18-carbon leukotoxin and isoleukotoxin. The diepoxide of linoleic acid can form tetrahydrofuran diols, sEH metabolizes
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1248-462: The organism. The C-term-EH catalyzes the addition of water to an epoxide to yield a vicinal diol (reaction 1). The Nterm-phos hydrolyzes phosphate monoesters, such as lipid phosphates, to yield alcohols and phosphoric acid (reaction 2). The C-term-EH hydrolyzes one important class of lipid signaling molecules that includes many epoxyeicosatrienoic acids (EETs) that have vasoactive, anti-inflammatory and analgesic properties. sEH also appears to be
1287-653: The possible therapeutic value of sEH inhibition comes from studies examining physiologically relevant single nucleotide polymorphisms (SNPs) of sEH in human populations. The Coronary Artery Risk Development in Young Adults (CARDIA) and the Atherosclerosis Risk in Communities (ARIC) studies both associated SNPs in the sEH coding region with coronary heart disease. In these studies, two nonsynonymous SNPs were identified, R287Q and K55R. R287Q changes
1326-403: The regulation of hypertension can be used as a simple model of sEH function in the kidney. Here the EETs are vasodilatory , and can be thought of as balancing other vasoconstrictive signals. sEH hydrolyzes the EETs to form the dihydroxyeicosatrienoic acids (DHETs). These molecules are more water-soluble and are more easily metabolized by other enzymes, so the vasodilatory signal is removed from
1365-618: The sEH pathway is generally considered to limit the actions of the hepoxilins. The phosphatase activity of sEH has been shown to hydrolyze in vitro lipid phosphates such as terpene pyrophosphates or lysophosphatidic acids . Studies suggest a potential role of sEH in regulating cholesterol biosynthesis and metabolism in the brain. If the N-terminal domain of sEH is regulating cholesterol metabolism, it emplies that higher levels of its phosphatase activity could potentially increase brain cholesterol concentrations. However, its biological role
1404-563: The site of action through excretion, tipping the balance of vasoconstrictive and vasodilatory signals towards vasoconstriction. This change in the lipid signaling increases vascular resistance to blood flow and blood pressure. By reducing sEH epoxide hydrolase activity, and thereby shutting off the major route of metabolism of the EETs, the levels of these molecules can be stabilized or increased, increasing blood flow and reducing hypertension. This reduction in sEH activity can be achieved in genetic models in which sEH has been knocked out, or through
1443-403: The terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems . The term "P450" is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm ) when it is in the reduced state and complexed with carbon monoxide . Most P450s require a protein partner to deliver one or more electrons to reduce
1482-452: The use of small molecule sEH inhibitors. This simplified model is complicated by a number of factors in vivo. The EETs display different properties in different vascular beds. The DHETs are more readily excreted, but they have yet to be fully characterized, and may possess biological properties themselves, complicating the balance of signals described in the simplified model. There are epoxides of other lipids besides arachidonic acid such as
1521-417: Was first named cytosolic epoxide hydrolase; however, after its discovery inside the peroxisomes of some organs, it was renamed soluble epoxide hydrolase or sEH. sEH has a restricted substrate selectivity, and has not been shown to hydrolyze any toxic or mutagenic xenobiotics . Conversely, the sEH plays a major role in the in vivo metabolism of endogenous lipid epoxides, such as the EETs and squalene oxide ,
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