Inhibition, Cyclooxygenase activity

50-78-2

BSYNRYMUTXBXSQ-UHFFFAOYSA-N

Aspirin

Acetylsalicylic acid Benzoic acid, 2-(acetyloxy)- 2-(ACETYLOXYBENZOIC) ACID 2-(Acetyloxy)benzoic acid 2-Acetoxybenzoic acid 2-Carboxyphenyl acetate A.S.A. Empirin Acenterine Acetard Aceticyl Acetilum acidulatum Acetisal Acetonyl Acetophen Acetosal Acetosalic acid Acetosalin Acetylin Acetylsal ACETYLSALICYLSAEURE Acetyonyl Acetysal Acide O-acetylsalicylique acido O-acetilsalicilico Acidum acetylsalicylicum Acimetten Acylpyrin Albyl E Asaflow Asagran Asatard Ascolong Ascriptin Aspalon Aspergum Aspirdrops Aspirina 03 Aspirin-Direkt Aspro Clear Aspropharm Asteric Benaspir Bialpirina Bialpirinia Cardioaspirina Claradin Colfarit Contrheuma Retard Coricidin Coricidin D Dolean pH 8 Dominal Duramax Easprin Ecotrin Empirin Endosprin Endydol Entericin Enterophen Enterosarine Entrophen Gelprin Globentyl Globoid Helicon Idragin Istopirin Kapsazal Magnecyl Measurin Medisyl Melhoral Micristin Miniasal Neuronika NSC 27223 NSC 406186 Nu-seals o-(Acetyloxy)benzoic acid o-Acetoxybenzoic acid O-acetylsalicylic acid O-Acetylsalicylsaure o-Carboxyphenyl acetate Persistin Polopiryna Rheumintabletten Rhodine Rhodine 2312 Rhodine NC RP Salacetin Salcetogen Saletin Salicylic acid acetate SALICYLIC ACID, ACETYL- Salospir Salycylacetylsalicylic acid Solpyron Temperal Triple-sal Trombyl Zorprin

DTXSID5020108

15307-79-6

KPHWPUGNDIVLNH-UHFFFAOYSA-M

Diclofenac sodium

Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-, monosodium salt [2-[(2,6-dichlorophenyl)amino]phenyl]acetate de sodium [2-[(2,6-diclorofenil)amino]fenil]acetato de sodio [o-(2,6-Dichloroanilino)phenyl]acetic acid sodium salt {2-[(2,6-Dichlorophenyl)amino]phenyl}acetate de sodium 2-(2,6-Dichloroanilino)phenylacetic acid sodium salt 2-[(2,6-Dichlorophenyl)amino]benzene acetic acid monosodium salt Acetic acid, [o-(2,6-dichloroanilino)phenyl]-, monosodium salt Allvoran Assaren Benfofen Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-, sodium salt (1:1) Cataflam Delphimix Diacron Dichronic Diclobene Diclobenin Diclodyn Diclofen SR 100 Diclofenac sodium salt Diclofenac-Na Emulgel Diclofenacsodium Emulgel Diclokalium Diclophenac sodium Diclo-Phlogont Diclo-Puren Diclord Diclorep Dicloreum Diklovit Dolobasan Duravolten Dyloject Effekton Evofenac Feloran Fortfen Hyanalgese D Inflaban Kriplex N-(2,6-Dichlorophenyl)-o-aminophenylacetic acid sodium salt Natrium-[2-[(2,6-dichlorphenyl)amino]phenyl]acetat Neriodin Novapirina Orthofen Orthophen Primofenac Profenac Prophenatin Rhumalgan sodium [2-[(2,6-dichlorophenyl)amino]phenyl]acetate Sodium [o-(2,6-dichloroanilino)phenyl]acetate Sodium 2-(2,6-dichloroanilino)-phenyl-acetate Sodium diclofenac Sorelmon Tsudohmin Valetan Voltaren Voltaren Ophtha Voltaren Ophtha CD Voltarol Voveran

DTXSID3037208

53-86-1

CGIGDMFJXJATDK-UHFFFAOYSA-N

1-(p-Chlorobenzoyl)-5-methoxy-2-methyl-Indole-3-acetic acid

1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl- [1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid 1-(4-Chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetic acid 1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 1-(4-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid 1-(p-Chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid 1-(p-Chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetic acid 1-(p-Chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid 1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid Artracin Artrinovo Artrivia Bonidin Bonidon Gel Chibro-Amuno Chrono-Indicid Chrono-Indocid 75 Confortid Dolcidium Dolcidium PL Dolovin Durametacin Elmetacin Idomethine Imbrilon Indacin Indocid Indocin Indocollyre Indole-3-acetic acid, 1-(p-chlorobenzoyl)-5-methoxy-2-methyl- Indomecol Indomed Indomee indometacin indometacina Indometacine Indomethacine Indomethine Indomod Indonol Indo-Phlogont Indoptic Indoptol Indo-Rectolmin Indorektal IndoRich Indo-Tablinen Indoxen Inflazon Infrocin Innamit Inteban Inteban SP Metacen Metartril Methazine Metindol Mezolin Mikametan Mobilan N-(p-Chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid NSC 77541 Reumacide Rheumacin LA Sadoreum Vital Vitacid α-[1-(p-Chlorobenzoyl)-2-methyl-5-methoxy-3-indolyl]acetic acid

DTXSID9020740

22204-53-1

CMWTZPSULFXXJA-VIFPVBQESA-N

Naproxen

2-Naphthaleneacetic acid, 6-methoxy-α-methyl-, (αS)- (+)-(S)-Naproxen (+)-2-(6-Methoxy-2-naphthyl)propionic acid (+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid (+)-Naproxen (S)-(+)-2-(6-Methoxy-2-naphthyl)propionic acid (S)-(+)-Naproxen (S)-(+)-Naproxene (S)-2-(6-Methoxy-2-naphthyl)propanoic acid (S)-2-(6-Methoxy-2-naphthyl)propionic acid (S)-2-(6-Methoxynaphthalen-2-yl)propanoic acid (S)-2-(6-Methoxynaphthalen-2-yl)propionic acid (S)-6-Methoxy-α-methyl-2-naphthaleneacetic acid (S)-Naproxen (S)-α-Methyl-6-methoxynaphthalene-2-acetic acid 2-Naphthaleneacetic acid, 6-methoxy-α-methyl-, (+)- 2-Naphthaleneacetic acid, 6-methoxy-α-methyl-, (S)- Apo-Naproxen Aproxen d-2-(6-Methoxy-2-naphthyl)propionic acid Diocodal d-Naproxen Dysmenalgit Equiproxen Floginax Laraflex Naprium Naprius Naprosyn Naprosyne naproxene naproxeno Nycopren Panoxen Proxine Veradol

DTXSID4040686

15687-27-1

HEFNNWSXXWATRW-UHFFFAOYNA-N

HEFNNWSXXWATRW-UHFFFAOYSA-N

Ibuprofen

Benzeneacetic acid, α-methyl-4-(2-methylpropyl)- (.+-.)-2-(p-Isobutylphenyl)propionic acid (.+-.)-Ibuprofen (.+-.)-Ibuprophen (.+-.)-α-Methyl-4-(2-methylpropyl)benzeneacetic acid (4-Isobutylphenyl)-α-methylacetic acid (RS)-Ibuprofen 2-(4-Isobutylphenyl)propanoic acid 2-(4'-Isobutylphenyl)propionic acid 2-(4-Isobutylphenyl)propionic acid 2-(p-Isobutylphenyl)propionic acid 4-Isobutylhydratropic acid 4-Isobutyl-α-methylphenylacetic acid Actiprofen Algi-Flanderil Algiflex Algofen Amibufen Anflagen Antarene Antiflam Apo-Ibuprofen Apsifen Artofen Balkaprofen Betaprofen Brufanic Brufen Retard Bruflam Brufort Buburone Buluofen Butacortelone Butylenin Codral Period Pain Combiflam Dansida Dentigoa Dibufen dl-Ibuprofen Dolgirid Dolmaral Dolocyl Dolo-Dolgit Dolofen Dolofen F Dolomax Donjust B Doretrim Dorival Easifon Epobron Femadon Fenspan Gynofug Haltran Hydratropic acid, p-isobutyl- Ibosure Ibu-Attritin Ibuflamar Ibugesic Ibuleve Ibulgan Ibumetin Ibupirac Ibupril Ibuprocin Ibuprofene ibuprofeno Ibuprohm Ibu-slow Ibu-Tab Inabrin Iprogel Lamidon Librofem Lidifen Mensoton Motrin IB Mynosedin Nagifen-D Napacetin Nobafon Nobfelon Noritis Novogent Novoprofen NSC 256857 Nurofen Optifen Opturem Ostarin Ostofen p-(2-Methylpropyl)-α-methylphenylacetic acid Paduden Panafen Pantrop Paxofen Pediaprofen Perofen PHENYLACETIC ACID, 2-METHYL-4-(2-METHYLPROPYL)- p-Isobutyl-2-phenylpropionic acid p-Isobutylhydratropic acid Proartinal Proflex Prontalgin Quadrax Ranofen Recidol Relcofen Roidenin Seclodin Suspren Syntofene Tabalon Tabalon 400 Tatanal Trendar Unipron Uprofen α-(4-Isobutylphenyl)propionic acid α-Methyl-4-(2-methylpropyl)benzeneacetic acid

DTXSID5020732

155569-91-8

Emamectin benzoate

4''-Epimethylamino-4''-deoxyavermectin B1a and B1b benzoates Avermectin B1, 4''-deoxy-4''-(methylamino)-, (4''R)-, benzoate (1:1)

DTXSID0034566

100-00-5

CZGCEKJOLUNIFY-UHFFFAOYSA-N

1-Chloro-4-nitrobenzene

Benzene, 1-chloro-4-nitro- p-Chloronitrobenzene 4-Chloronitrobenzene 1-Chlor-4-nitrobenzol 1-cloro-4-nitrobenceno 1-Nitro-4-chlorobenzene 4-Chloro-1-nitrobenzene 4-Nitro-1-chlorobenzene 4-Nitrochlorobenzene 4-Nitrophenyl chloride NSC 9792 P-CHLORNITROBENZOL p-Nitrochlorobenzene p-Nitrophenyl chloride

DTXSID5020281

169590-42-5

RZEKVGVHFLEQIL-UHFFFAOYSA-N

Celecoxib

Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]- 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide Celebra Celebrex Celecox Celocoxib

DTXSID0022777

112281-77-3

LQDARGUHUSPFNL-UHFFFAOYNA-N

LQDARGUHUSPFNL-UHFFFAOYSA-N

Tetraconazole

1H-1,2,4-Triazole, 1-{2-(2,4-dichlorophenyl)-3-(1,1,2,2-tetrafluoroethoxy)propyl}-, (.+-.)-

DTXSID8034956

2058-46-0

UBDNTYUBJLXUNN-IFLJXUKPSA-N

Oxytetracycline hydrochloride

2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-, (4S-(4.alpha.,4a.alpha.,5.alpha.,5a.alpha.,6.beta.,12a.alpha.))-

DTXSID5021097

PR:000013427

PR prostaglandin G/H synthase 1

PR:000013428

PR prostaglandin G/H synthase 2

CHEBI:15551

CHEBI prostaglandin E2

CHEBI:39124

CHEBI calcium ion

CHEBI:17544

CHEBI hydrogencarbonate

UBERON:0005079

UBERON eggshell

GO:0004666

GO prostaglandin-endoperoxide synthase activity

GO:0006816

GO calcium ion transport

GO:0015701

GO bicarbonate transport

GO:0044703

GO multi-organism reproductive process

WIKI decreased

WIKI functional change

WIKI abnormal

Aceytlsalicylic acid

2016-11-29T18:42:08

Diclofenac sodium

2016-11-29T18:42:09

Indomethacin

2016-11-29T18:42:17

Naproxen

2016-11-29T18:42:20

Ibuprofen

2016-11-29T18:42:26

Emamectin benzoate

2016-11-29T18:42:26

1-Chloro-4-nitrobenzene

2016-11-29T18:42:26

169590-42-5

2016-11-29T18:42:26

Celecoxib

2016-11-29T18:42:26

3-(Difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]-1H-pyrazole

2016-11-29T18:42:26

Tetraconazole

2016-11-29T18:42:26

2058-46-0

2016-11-29T18:42:27

Oxytetracycline hydrochloride

2016-11-29T18:42:27

Sodium (4-fluoro-2-{[(1S)-1-phenylpropyl]carbamoyl}phenyl)(quinolin-8-ylsulfonyl)azanide

2016-11-29T18:42:27

Inhibition, Cyclooxygenase activity

Molecular

Prostaglandin-endoperoxide synthase (PTGS; KEGG ID E.C. 1.14.99.1; <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.genome.jp/dbget-bin/www_bget?ec:1.14.99.1">[1]</a>) is an enzyme that has two catalytic sites. Cyclooxygenase site (COX) catalyzes conversion of arachidonic acid into endoperoxide prostaglandin G2 (<a href="/wiki/index.php?title=Simmons_et_al.,_2004&action=edit&redlink=1" class="new" title="Simmons et al., 2004 (page does not exist)">Simmons et al., 2004</a>). Peroxidase active site converts PGG2 to PGH2 (KEGG reactions 1599, 1590, <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.genome.jp/dbget-bin/www_bget?rn:R01599+R01590+R00073">[2]</a>). PGH2 is a precursor for synthesis of other prostaglandins (e.g., PGEs, PGFs; <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.genome.jp/kegg-bin/show_pathway?scale=1.0&query=prostaglandin&map=map00590&scale=&auto_image=&show_description=hide&multi_query">[3]</a>), 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).

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). <ul> <li>COX1 activity - US EPA ToxCast assay id: NVS_ENZ_oCOX1 </li> <li>COX2 activity - US EPA ToxCast assay id: NVS_ENZ_oCOX2 </li> </ul>

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).

CL:0000255

CL eukaryotic cell

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. AOPWiki 2016-11-29T18:41:22

2017-09-16T10:14:42

Reduction, Prostaglandin E2 concentration

Tissue

UBERON:0000178

UBERON blood

AOPWiki 2016-11-29T18:41:23

2017-09-16T10:14:43

Reduction, Ca and HCO3 transport to shell gland

Tissue

UBERON:0008975

UBERON oviduct shell gland

AOPWiki 2016-11-29T18:41:22

2017-09-16T10:14:43

Reduction, Eggshell thickness

Tissue

UBERON:0005079

UBERON eggshell

AOPWiki 2016-11-29T18:41:22

2017-09-16T10:14:43

N/A, Gap

Tissue

Do NOT enter any biological descriptions for this key event! This key event is intended as a placeholder for cases where there is a known gap of knowledge that should be noted in an AOP. If you would like to include information specific to your AOP when using this key event, you can include that information on the key event relationship pages that connect this key event to the key events in your AOP.

UBERON:0005079

UBERON eggshell

AOPWiki 2016-11-29T18:41:22

2017-09-16T10:14:44

N/A, Reproductive failure

Individual

AOPWiki 2016-11-29T18:41:23

2016-12-03T16:37:49

<upstream-id>a32ba461-2991-4fcc-9ea4-f4eeb06c0533</upstream-id> <downstream-id>fadaecfc-b119-4902-a3c3-bba07a5875a2</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eaf4f5a8> AOPWiki 2016-11-29T18:41:33

2016-12-03T16:37:54

<upstream-id>fadaecfc-b119-4902-a3c3-bba07a5875a2</upstream-id> <downstream-id>780e2e3b-7c5d-422a-a65f-930f47db3b3b</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eafaeff8> AOPWiki 2016-11-29T18:41:33

2016-12-03T16:37:55

<upstream-id>780e2e3b-7c5d-422a-a65f-930f47db3b3b</upstream-id> <downstream-id>77b7d504-3104-4bfc-918e-9c4cf3f12cb2</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eafc1680> AOPWiki 2016-11-29T18:41:33

2016-12-03T16:37:55

<upstream-id>77b7d504-3104-4bfc-918e-9c4cf3f12cb2</upstream-id> <downstream-id>3225e155-31bc-4a27-8bf2-3537731095db</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eafe4450> AOPWiki 2016-11-29T18:41:33

2016-12-03T16:37:54

<upstream-id>3225e155-31bc-4a27-8bf2-3537731095db</upstream-id> <downstream-id>1443d7cf-0f8e-4827-958f-9044f5f731fd</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42eb013ed0> AOPWiki 2016-11-29T18:41:33

2016-12-03T16:37:55

Cyclooxygenase inhibition leading reproductive failure

Agnes Aggy

Dan Villeneuve, US EPA Mid-Continent Ecology Division (villeneuve.dan@epa.gov)

BY-SA

1.29

1.0

Non-steroidal anti-inflammatory drugs have been specifically designed to inhibit cyclooxygenase active site of PTGS; these mechanisms of inhibition are well characterized (Simmons et al, 2004). NSAIDs interfere with COX site via multiple mechanisms including competitive inhibition (most NSAIDs compete for active site with arachidonic acid) and covalent modification (irreversible acetylation) of COX (e.g., aspirin) (Simmons et al., 2004; Willoughby et al., 2011). NSAIDs display different levels of selectivity for the COX-1 vs. COX-2 isoforms (Simmons et al., 2004). Majority of NSAIDs inhibit both isoforms (with variable levels of selectivity for COX-1 vs. COX-2), but several have been designed to preferentially inhibit COX-2 (Bacchi et al., 2012). Recently, COX-1 specific inhibitors have been developed and their therapeutic potential is being explored (Liedtke et al., 2012). Most extensive evidence regarding chemical initiation of this event comes from the mammalian literature and relates to NSAIDs. In addition to NSAIDs, common environmental contaminants of diverse chemical structures and uses (e.g., parabens, phthalates, benzophenones) have been postulated to inhibit prostaglandin synthesis via COX inhibition (Kristensen et al., 2011). U.S. EPA’s high throughput screening program (ACToR, epa.gov) indicated COX as a frequent contaminant target - 61% of 143 tested chemicals inhibited COX-1 and 59% of 106 inhibited COX-2 activity. Several chemicals were either similar in potency (e.g., monobutylphthalate) or more potent than NSAIDs (e.g., insecticide emamectin benzoate and industrial intermediary 1-Chloro-4-nitrobenzene were more potent inhibitors of COX2 than NSAID celecoxib, which was specifically designed to inhibit COX-2). Mechanisms of inhibition for these chemicals are not well elucidated.

adjacent

Not Specified

Moderate adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Moderate adjacent

Not Specified

High

Consider the following criteria (may include references to KE Relationship pages): 1. concordance of dose-response relationships; 2. temporal concordance among the key events and adverse effect; 3. strength, consistency, and specificity of association of adverse effect and initiating event; 4. biological plausibility, coherence, and consistency of the experimental evidence; 5. alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP. It should be noted that alternative mechanisms of action, if supported, require a separate AOP; 6. uncertainties, inconsistencies and data gaps.

AOPWiki 2016-11-29T18:41:16

2023-09-25T16:26:45