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Event: 79

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Inhibition, Cyclooxygenase activity

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Inhibition, Cyclooxygenase activity
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
prostaglandin-endoperoxide synthase activity prostaglandin G/H synthase 1 decreased
prostaglandin-endoperoxide synthase activity prostaglandin G/H synthase 2 decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Cyclooxygenase inhibition leading reproductive failure MolecularInitiatingEvent Dan Villeneuve (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 2 MolecularInitiatingEvent Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 3 MolecularInitiatingEvent Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 5 MolecularInitiatingEvent Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 1 MolecularInitiatingEvent Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition 4 MolecularInitiatingEvent Dalma Martinovic-Weigelt (send email) Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Prostaglandin-endoperoxide synthase (PTGS; KEGG ID E.C. 1.14.99.1; [1]) is an enzyme that has two catalytic sites. Cyclooxygenase site (COX) catalyzes conversion of arachidonic acid into endoperoxide prostaglandin G2 (Simmons et al., 2004). Peroxidase active site converts PGG2 to PGH2 (KEGG reactions 1599, 1590, [2]). PGH2 is a precursor for synthesis of other prostaglandins (e.g., PGEs, PGFs; [3]), prostacyclin and thromboxanes (Simmons et al., 2004; Botting and Botting 2011). Two of the COX isoforms (COX-1 and COX-2) encoded by two different genes (ptgs1 and ptgs2) are well characterized. Ptgs1 is typically expressed constitutively and is involved in maintenance of homeostatic functions. Ptgs2 is largely inducible (e.g., by inflammation, during discrete stages of gamete maturation etc.), but can also be constitutively expressed (e.g., kidney; Green et al, 2012). In mammals, COX-3 (a splice of COX-1) has also been identified (Chandrasekharan et al., 2002), but its function is not well characterized and it is not likely to have prostaglandin producing capacity (Bacchi et al., 2012).

Most COX inhibitors interfere with COX site via competitive inhibition (compete for active site with arachidonic acid), but some are capable of covalent modification of COX (Simmons et al., 2004; Willoughby et al., 2011). The inhibition of COX can lead to reduced efficiency of converting arachidonic acid to PGG2. Therefore inhibition of COX can decrease the rate of prostaglandin production (reviewed Simmons et al, 2004; Bacchi et al., 2012).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Multiple methods have been developed to investigate inhibition of COX activity - the cyclooxygenase (COX) reaction can be monitored by measurement of oxygen consumption, peroxidase co-substrate oxidation or prostaglandin (PG) detection (e.g., Jang and Pezzuto, 1997; Cuendet et al., 2006). Commercial kits from many suppliers deploying a variety of methods are available for purchase (e.g., Cayman Chemicals, Ann Arbor, MI). Repeatability and reproducibility of these commercial assays is well documented – the data generated by assays is reproducible and interassay variation is typically below 5%. The preparation of fish ovarian tissue for COX activity assay is described by Lister and Van der Kraak (2008).

  • COX1 activity - US EPA ToxCast assay id: NVS_ENZ_oCOX1
  • COX2 activity - US EPA ToxCast assay id: NVS_ENZ_oCOX2

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

There is a high level of conservation of this molecular target (i.e., COX), as well as its function, especially across vertebrates (Havird et al., 2008, 2015), indicating that many vertebrate taxa may be susceptible to COX inhibition. Typically, teleost fish genomes contain more than one COX-1 and/or COX -2 gene, likely a result of genome duplication after divergence of teleosts from tetrapods (e.g., Ishikawa et al., 2007; Havird et al., 2015). In invertebrates, COX is found in most crustaceans, the majority of molluscs, but only in specific taxa/lineages within Cnidaria and Annelida. COX genes are not found in Hemichordata, Echinodermata, or Platyhelminthes. Insecta COX genes lack in homology, but may function as COX enzymes based on structural analyses (Havird et al., 2015).

References

List of the literature that was cited for this KE description. More help

Bacchi, S., Palumbo, P., Sponta, A., & Coppolino, M. F. (2012). Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents), 11(1), 52-64.

Botting, R. M., & Botting, J. H. (2011). C14 Non-steroidal anti-inflammatory drugs. In Principles of Immunopharmacology (pp. 573-584). Birkhäuser Basel.

Cao, H., Yu, R., Tao, Y., Nikolic, D., & van Breemen, R. B. (2011). Measurement of cyclooxygenase inhibition using liquid chromatography–tandem mass spectrometry. Journal of pharmaceutical and biomedical analysis, 54(1), 230-235.

Chandrasekharan, N. V., Dai, H., Roos, K. L. T., Evanson, N. K., Tomsik, J., Elton, T. S., & Simmons, D. L. (2002). COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proceedings of the National Academy of Sciences,99(21), 13926-13931.

Cuendet, M., Mesecar, A. D., DeWitt, D. L., & Pezzuto, J. M. (2006). An ELISA method to measure inhibition of the COX enzymes. Nature protocols,1(4), 1915-1921. Green, T., Gonzalez, A. A., Mitchell, K. D., & Navar, L. G. (2012). The Complex Interplay between COX-2 and Angiotensin II in Regulating Kidney Function. Current opinion in nephrology and hypertension, 21(1), 7.

Havird, J. C., Kocot, K. M., Brannock, P. M., Cannon, J. T., Waits, D. S., Weese, D. A., ... & Halanych, K. M. (2015). Reconstruction of Cyclooxygenase Evolution in Animals Suggests Variable, Lineage-Specific Duplications, and Homologs with Low Sequence Identity. Journal of molecular evolution, 1-16.

Havird, J. C., Miyamoto, M. M., Choe, K. P., & Evans, D. H. (2008). Gene duplications and losses within the cyclooxygenase family of teleosts and other chordates. Molecular biology and evolution, 25(11), 2349-2359.

Ishikawa, T. O., Griffin, K. J., Banerjee, U., & Herschman, H. R. (2007). The zebrafish genome contains two inducible, functional cyclooxygenase-2 genes.Biochemical and biophysical research communications, 352(1), 181-187.

Jang, M. S., & Pezzuto, J. M. (1997). Assessment of cyclooxygenase inhibitors using in vitro assay systems. Methods in cell science, 19(1), 25-31.

Kristensen, D. M., Skalkam, M. L., Audouze, K., Lesné, L., Desdoits-Lethimonier, C., Frederiksen, H., ... & Leffers, H. (2011). Many putative endocrine disruptors inhibit prostaglandin synthesis. Environmental health perspectives, 119(4), 534-41.

Liedtke, A. J., Crews, B. C., Daniel, C. M., Blobaum, A. L., Kingsley, P. J., Ghebreselasie, K., & Marnett, L. J. (2012). Cyclooxygenase-1-selective inhibitors based on the (E)-2′-des-methyl-sulindac sulfide scaffold. Journal of medicinal chemistry, 55(5), 2287-2300.

Lister, A. L., & Van Der Kraak, G. (2008). An investigation into the role of prostaglandins in zebrafish oocyte maturation and ovulation. General and comparative endocrinology, 159(1), 46-57.

Simmons, D. L., Botting, R. M., & Hla, T. (2004). Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological reviews,56(3), 387-437.

Willoughby, D. A., Moore, A. R., & Colville-Nash, P. R. (2000). COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease. The Lancet, 355(9204), 646-648.