Cyclooxygenase, Lipoxygenase, and Epoxygenase Pathways
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Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 231 _____________________________ _____________________________ Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21 BY JOHAN BYLUND ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2000 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutical Pharmacology presented at Uppsala University in 2000 ABSTRACT Bylund, J. 2000. Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid: Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from Faculty of Pharmacy 231 50 pp. Uppsala. ISBN 91-554-4784-8. Cytochrome P450 (P450 or CYP) is an enzyme system involved in the oxygenation of a wide range of endogenous compounds as well as foreign chemicals and drugs. This thesis describes investigations of P450-catalyzed oxygenation of prostaglandins, linoleic and arachidonic acids. The formation of bisallylic hydroxy metabolites of linoleic and arachidonic acids was studied with human recombinant P450s and with human liver microsomes. Several P450 enzymes catalyzed the formation of bisallylic hydroxy metabolites. Inhibition studies and stereochemical analysis of metabolites suggest that the enzyme CYP1A2 may contribute to the biosynthesis of bisallylic hydroxy fatty acid metabolites in adult human liver microsomes. 19R-Hydroxy-PGE and 20-hydroxy-PGE are major components of human and ovine semen, respectively. They are formed in the seminal vesicles, but the mechanism of their biosynthesis is unknown. Reverse transcription-polymerase chain reaction using degenerate primers for mammalian CYP4 family genes, revealed expression of two novel P450 genes in human and ovine seminal vesicles. -
Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers S
Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/03/17/jpet.116.232108.DC1 1521-0103/357/3/529–536$25.00 http://dx.doi.org/10.1124/jpet.116.232108 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:529–536, June 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers s Sumanta Kumar Goswami, Debin Wan, Jun Yang, Carlos A. Trindade da Silva, Christophe Morisseau, Sean D. Kodani, Guang-Yu Yang, Bora Inceoglu, and Bruce D. Hammock Department of Entomology and Nematology, and Comprehensive Cancer Center (S.K.G., D.W., J.Y., C.A.T.S., C.M., S.D.K., B.I., B.D.H.), University of California–Davis, Davis, California; Department of Genetics and Biochemistry (C.A.T.S.), Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil; Department of Pathology (G.-Y.Y.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois Downloaded from Received January 13, 2016; accepted March 16, 2016 ABSTRACT Proton pump inhibitors such as omeprazole (OME) reduce the with OME (20 mg/kg, PO). In addition, the effect of treatment was severity of gastrointestinal (GI) ulcers induced by nonsteroidal studied on levels of Hb in blood, EETs in plasma, inflammatory jpet.aspetjournals.org anti-inflammatory drugs (NSAIDs) but can also increase the markers such as myeloperoxidase (MPO) in intestinal tissue chance of dysbiosis. The aim of this study was to test the homogenates, and tissue necrosis factor-a (TNF-a) in serum. -
Eicosanoids Mediate Insect Nodulation Responses to Bacterial Infections (Cyclooxygenase/Lipoxygenase/Phospholipase A2/Manduca Sexta/Serratia Marcescens) JON S
Proc. Natl. Acad. Sci. USA Vol. 91, pp. 12418-12422, December 1994 Physiology Eicosanoids mediate insect nodulation responses to bacterial infections (cyclooxygenase/lipoxygenase/phospholipase A2/Manduca sexta/Serratia marcescens) JON S. MILLER, TUANH NGUYEN, AND DAVID W. STANLEY-SAMUELSON* Insect Biochemistry/Physiology Laboratory, Department of Entomology, University of Nebraska, Lincoln, NE 68583-0816 Communicated by Wendell L. Roelofs, September 12, 1994 (receivedfor review August 11, 1993) ABSTRACT We propose that nodule formation is medi- inhibiting eicosanoid biosynthesis. On the basis of these ated by eicosanoids in insects. Nodulation is the temporally and findings, we proposed that eicosanoid products of the cyclo- quantitatively predominant cellular defense response to bac- oxygenase and lipoxygenase pathways are involved in insect terial infection in insects and other invertebrates. Inhibition of immune responses to bacterial infections. Because most of eicosanoid biosynthesis in larvae of the tobacco hornworn our experiments were done during the first hour postinfection Manduca sexta immediately prior to intrahemocoelic infections (PI), long before the appearance of antibacterial proteins in with the bacterium Serratia marcescens strongly reduced the insect hemolymph, we suggested that eicosanoids mediate nodulation response. Inhibition of eicosanoid biosynthesis also one or more hemocytic defense responses (6). reduced formation of cellular aggregates at 1 hr postinfection, This suggestion opens a crucial question: which -
Synonymous Single Nucleotide Polymorphisms in Human Cytochrome
DMD Fast Forward. Published on February 9, 2009 as doi:10.1124/dmd.108.026047 DMD #26047 TITLE PAGE: A BIOINFORMATICS APPROACH FOR THE PHENOTYPE PREDICTION OF NON- SYNONYMOUS SINGLE NUCLEOTIDE POLYMORPHISMS IN HUMAN CYTOCHROME P450S LIN-LIN WANG, YONG LI, SHU-FENG ZHOU Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, P. R. China (LL Wang & Y Li) Discipline of Chinese Medicine, School of Health Sciences, RMIT University, Bundoora, Victoria 3083, Australia (LL Wang & SF Zhou). 1 Copyright 2009 by the American Society for Pharmacology and Experimental Therapeutics. DMD #26047 RUNNING TITLE PAGE: a) Running title: Prediction of phenotype of human CYPs. b) Author for correspondence: A/Prof. Shu-Feng Zhou, MD, PhD Discipline of Chinese Medicine, School of Health Sciences, RMIT University, WHO Collaborating Center for Traditional Medicine, Bundoora, Victoria 3083, Australia. Tel: + 61 3 9925 7794; fax: +61 3 9925 7178. Email: [email protected] c) Number of text pages: 21 Number of tables: 10 Number of figures: 2 Number of references: 40 Number of words in Abstract: 249 Number of words in Introduction: 749 Number of words in Discussion: 1459 d) Non-standard abbreviations: CYP, cytochrome P450; nsSNP, non-synonymous single nucleotide polymorphism. 2 DMD #26047 ABSTRACT Non-synonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptivity to disease. Identification of deleterious nsSNPs from tolerant nsSNPs is important for characterizing the genetic basis of human disease, assessing individual susceptibility to disease, understanding the pathogenesis of disease, identifying molecular targets for drug treatment and conducting individualized pharmacotherapy. -
Colorectal Cancer and Omega Hydroxylases
1 The differential expression of omega-3 and omega-6 fatty acid metabolising enzymes in colorectal cancer and its prognostic significance Abdo Alnabulsi1,2, Rebecca Swan1, Beatriz Cash2, Ayham Alnabulsi2, Graeme I Murray1 1Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, AB25, 2ZD, UK. 2Vertebrate Antibodies, Zoology Building, Tillydrone Avenue, Aberdeen, AB24 2TZ, UK. Address correspondence to: Professor Graeme I Murray Email [email protected] Phone: +44(0)1224 553794 Fax: +44(0)1224 663002 Running title: omega hydroxylases and colorectal cancer 2 Abstract Background: Colorectal cancer is a common malignancy and one of the leading causes of cancer related deaths. The metabolism of omega fatty acids has been implicated in tumour growth and metastasis. Methods: This study has characterised the expression of omega fatty acid metabolising enzymes CYP4A11, CYP4F11, CYP4V2 and CYP4Z1 using monoclonal antibodies we have developed. Immunohistochemistry was performed on a tissue microarray containing 650 primary colorectal cancers, 285 lymph node metastasis and 50 normal colonic mucosa. Results: The differential expression of CYP4A11 and CYP4F11 showed a strong association with survival in both the whole patient cohort (HR=1.203, 95% CI=1.092-1.324, χ2=14.968, p=0.001) and in mismatch repair proficient tumours (HR=1.276, 95% CI=1.095-1.488, χ2=9.988, p=0.007). Multivariate analysis revealed that the differential expression of CYP4A11 and CYP4F11 was independently prognostic in both the whole patient cohort (p = 0.019) and in mismatch repair proficient tumours (p=0.046). Conclusions: A significant and independent association has been identified between overall survival and the differential expression of CYP4A11 and CYP4F11 in the whole patient cohort and in mismatch repair proficient tumours. -
Fatty Acids: Essential…Therapeutic
Volume 3, No.2 May/June 2000 A CONCISE UPDATE OF IMPORTANT ISSUES CONCERNING NATURAL HEALTH INGREDIENTS Written and Edited By: Thomas G. Guilliams Ph.D. FATTY ACIDS: Essential...Therapeutic Few things have been as confusing to both patient and health care provider as the issue of fats and oils. Of all the essential nutrients required for optimal health, fatty acids have not only been forgotten they have been considered hazardous. Health has somehow been equated with “low-fat” or “fat-free” for so long, to suggest that fats could be essential or even therapeutic is to risk credibility. We hope to give a view of fats that is both balanced and scientific. This review will cover the basics of most fats that will be encountered in dietary or supplemental protocols. Recommendations to view essential fatty acids in a similar fashion as essential vitamins and minerals will be combined with therapeutic protocols for conditions ranging from cardiovascular disease, skin conditions, diabetes, nerve related disorders, retinal disorders and more. A complete restoration of health cannot be accomplished until there is a restoration of fatty acid nutritional information among health care professionals and their patients. Fats- What are they? Dietary fats come to us from a variety of sources, but primarily in the form of triglycerides. That is, three fatty acid molecules connected by a glycerol backbone (see fatty acid primer page 3 for diagram). These fatty acids are then used as energy by our cells or modified into phospholipids to be used as cell or organelle membranes. Some fatty acids are used in lipoprotein molecules to shuttle cholesterol and fats to and from cells, and fats may also be stored for later use. -
Molecular Details of Prostaglandin Synthesis Catalyzed by Cyclooxygenase-2 and Its Inhibition by Aspirin
ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Molecular Details of Prostaglandin Synthesis Catalyzed by Cyclooxygenase-2 and Its Inhibition by Aspirin. Anna Cebrián Prats PhD program in Chemistry Supervisors: José Maria Lluch López Àngels González Lafont Departament de Química Facultad de Cièncias 2020 This is an article-based PhD Thesis. This dissertation is composed of a short overview of the work, followed by a copy of the papers already published. “But nature is always more subtle, more intricate, more elegant than what we are able to imagine.” Carl Sagan Contents List of Acronyms . v I Introduction 1 1 Introduction 3 1.1 Biological Overview . 3 1.1.1 Polyunsaturated Fatty Acids (PUFAs) . 4 1.1.2 Eicosanoids . 5 1.1.3 Prostanoids . 6 1.1.4 Role of PUFAs into inflammatory processes . 7 1.2 Prostaglandin Endoperoxide H Synthase . 9 1.2.1 PGHS-2 structure . 10 1.2.2 Substrates binding to COX active site . 11 1.3 Catalytic Reaction . 13 1.3.1 Reaction Mechanism in the COX active site . 14 1.3.2 Regioselectivity and Stereoselectiviy . -
Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain
1 Review 2 Clinical Implications of 20-Hydroxyeicosatetraenoic 3 Acid in the Kidney, Liver, Lung and Brain: An 4 Emerging Therapeutic Target 5 Osama H. Elshenawy 1, Sherif M. Shoieb 1, Anwar Mohamed 1,2 and Ayman O.S. El-Kadi 1,* 6 1 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada; 7 [email protected] (O.H.E.); [email protected] (S.M.S.); [email protected] (A.M.) 8 2 Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of 9 Medicine and Health Sciences, Dubai, United Arab Emirates 10 * Correspondence: [email protected]; Tel.: 780-492-3071; Fax: 780-492-1217 11 Academic Editor: Kishor M. Wasan 12 Received: 12 January 2017; Accepted: 15 February 2017; Published: 20 February 2017 13 Abstract: Cytochrome P450-mediated metabolism of arachidonic acid (AA) is an important 14 pathway for the formation of eicosanoids. The ω-hydroxylation of AA generates significant levels 15 of 20-hydroxyeicosatetraenoic acid (20-HETE) in various tissues. In the current review, we discussed 16 the role of 20-HETE in the kidney, liver, lung, and brain during physiological and 17 pathophysiological states. Moreover, we discussed the role of 20-HETE in tumor formation, 18 metabolic syndrome and diabetes. In the kidney, 20-HETE is involved in modulation of 19 preglomerular vascular tone and tubular ion transport. Furthermore, 20-HETE is involved in renal 20 ischemia/reperfusion (I/R) injury and polycystic kidney diseases. The role of 20-HETE in the liver is 21 not clearly understood although it represents 50%–75% of liver CYP-dependent AA metabolism, 22 and it is associated with liver cirrhotic ascites. -
Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study
pharmaceuticals Article Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study Melita Lonˇcari´c 1 , Ivica Strelec 1 , Valentina Pavi´c 2 , Domagoj Šubari´c 3, Vesna Rastija 3 and Maja Molnar 1,* 1 Faculty of Food Faculty Osijek, Josip Juraj Strossmayer University, 31000 Osijek, Croatia; [email protected] (M.L.); [email protected] (I.S.) 2 Department of Biology, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; [email protected] 3 Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; [email protected] (D.Š.); [email protected] (V.R.) * Correspondence: [email protected]; Tel.: +385-31-224-342 Received: 2 July 2020; Accepted: 15 July 2020; Published: 17 July 2020 Abstract: Lipoxygenases (LOXs) are a family of enzymes found in plants, mammals, and microorganisms. In animals and plants, the enzyme has the capability for the peroxidation of unsaturated fatty acids. Although LOXs participate in the plant defense system, the enzyme’s metabolites can have numerous negative effects on human health. Therefore, many types of research are searching for compounds that can inhibit LOXs. The best quantitative structure–activity relationship (QSAR) model was obtained using a Genetic Algorithm (GA). Molecular docking was performed with iGEMDOCK. The inhibition of lipoxygenase was in the range of 7.1 to 96.6%, and the inhibition of lipid peroxidation was 7.0–91.0%. Among the synthesized compounds, the strongest inhibitor of soybean LOX-3 (96.6%) was found to be 3-benzoyl- 7-(benzyloxy)-2H-chromen-2-one. -
Identification of the Cytochrome P450 Enzymes Responsible for the X
FEBS Letters 580 (2006) 3794–3798 Identification of the cytochrome P450 enzymes responsible for the x-hydroxylation of phytanic acid J.C. Komen, R.J.A. Wanders* Departments of Clinical Chemistry and Pediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Received 27 March 2006; revised 26 May 2006; accepted 30 May 2006 Available online 9 June 2006 Edited by Sandro Sonnino tanic acid occurs effectively by bacteria present in the rumen Abstract Patients suffering from Refsum disease have a defect in the a-oxidation pathway which results in the accumulation of of ruminants. phytanic acid in plasma and tissues. Our previous studies have Phytanic acid accumulates in patients with adult Refsum dis- shown that phytanic acid is also a substrate for the x-oxidation ease (ARD, MIM 266500) which is due to a defect in the a-oxi- pathway. With the use of specific inhibitors we now show that dation pathway caused by mutations in one of two genes members of the cytochrome P450 (CYP450) family 4 class are including the PAHX gene which codes for phytanoyl-CoA responsible for phytanic acid x-hydroxylation. Incubations with hydroxylase [2,3], and the PEX7 gene which codes for the microsomes containing human recombinant CYP450s (Super- PTS2 receptor [4]. The majority of ARD patients have muta- TM somes ) revealed that multiple CYP450 enzymes of the family tions in the PAHX gene. The increased levels of phytanic acid 4 class are able to x-hydroxylate phytanic acid with the follow- in plasma and tissues are thought to be the direct cause for the ing order of efficiency: CYP4F3A > CYP4F3B > CYP4F2 > pathology of the disease. -
Production of 8,11,14,17-Cis-Eicosatetraenoic Acid
Production of 8,11,14,17-cis-Eicosatetraenoic Acid (20:4ω-3) by a ∆5 and ∆12 Desaturase-Defective Mutant of an Arachidonic Acid-Producing Fungus Mortierella alpina 1S-4 Hiroshi Kawashimaa, Eiji Sakuradanib, Nozomu Kamadab, Kengo Akimotoa, Kyoko Konishia, Jun Ogawab, and Sakayu Shimizub,* aInstitute for Biomedical Research, Suntory Ltd., Shimamoto-cho, Osaka 618-0001, Japan, and bDivision of Applied Life Sci- ences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan ∆ ∆ ABSTRACT: A 5 and 12 desaturase-defective mutant of an there are large amounts of other C20 PUFA, such as AA, EPA, arachidonic acid-producing fungus, Mortierella alpina 1S-4, pro- and dihomo-γ-linolenic acid (DGLA), which are difficult to duced 8,11,14,17-cis-eicosatetraenoic acid (20:4ω3) intracellu- separate from 20:4ω3. During our studies on PUFA production larly when grown with linseed oil. Dihomo-γ-linolenic acid was involving AA-producing Mortierella fungi, we found 20:4ω3 the only C20 polyunsaturated fatty acid (4.9 wt% of total mycelial was formed (ca. 0.5 mg/mL of culture medium) as a by-prod- ω fatty acids) other than 20:4 3. AA and 5,8,11,14,17-cis-eicosapen- uct (3). Large amounts of AA (2.44 mg/mL) and EPA (1.88 taenoic acid were not detected. The mycelial lipids consisted of mg/mL) were produced in this case. Recently, we reported 82.2% (by mol) triacylglycerol (TG), 7.1% diacylglycerol, 8.9% ω ∆ phospholipids (PL), and 1.9% free fatty acids. The percentage of 20:4 3 production by cultivating 5 desaturase-defective mu- 20:4ω3 was higher in PL (30.1%) than in TG (11.6%), and highest tants of AA-producing M. -
Cytochrome P450 Expression and Activities in Human Tongue Cells and Their Modulation by Green Tea Extract
Cytochrome P450 expression and activities in human tongue cells and their modulation by green tea extract By: Shin-Pei Yang, and Gregory M. Raner Yang, S.-P. and Raner, G.M. Cytochrome P450 Expression, Induction and Activities in Human Tongue Cells and their Modulation by Green Tea Extract, Toxicol. Appl. Pharmacol. 202, 140-150 (2005). DOI: 10.1016/j.taap.2004.06.014 Made available courtesy of Elsevier: http://www.elsevier.com/wps/find/homepage.cws_home ***Reprinted with permission. No further reproduction is authorized without written permission from Elsevier. This version of the document is not the version of record. Figures and/or pictures may be missing from this format of the document.*** Abstract: The expression, inducibility, and activities of several cytochrome P450 (CYP) enzymes were investigated in a human tongue carcinoma cell model, CAL 27, and compared with the human liver model HepG2 cells. The modulation effects of green tea on various CYP isoforms in both cell lines were also examined. RT-PCR analysis of CAL 27 cells demonstrated constitutive expression of mRNA for CYPs 1A1, 1A2, 2C, 2E1, 2D6, and 4F3. The results were negative for CYP2A6, 2B6/7, 3A3/4, and 3A7. Both cell lines displayed identical expression and induction profiles for all of the isoforms examined in this study except 3A7 and 2B6/7, which were produced constitutively in HepG2 but not Cal-27 cells. CYP1A1 and 1A2 were both induced by treatment with β-napthoflavone as indicated by RT-PCR and Western blotting, while CYP2C mRNA was upregulated by all-trans retinoic acid and farnesol.