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{{protein
{{redirect|COX||Cox (disambiguation)}}
|Name=[[PTGS1|prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)]]
{{enzyme
|caption=
| Name = prostaglandin-endoperoxide synthase
|image=
| EC_number = 1.14.99.1
| CAS_number = 9055-65-6
| IUBMB_EC_number = 1/14/99/1
| GO_code = 0004666
| image =
| width =
| caption =
}}
{{infobox protein
|Name=[[PTGS1|cyclooxygenase 1]]
|caption=Crystallographic structure of prostaglandin H2 synthase-1 complex with [[flurbiprofen]].<ref name="pmid8121489">{{PDB|1CQE}}; {{cite journal | vauthors = Picot D, Loll PJ, Garavito RM | title = The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1 | journal = Nature | volume = 367 | issue = 6460 | pages = 243–9 | date = Jan 1994 | pmid = 8121489 | doi = 10.1038/367243a0 }}</ref>
|image= PROSTAGLANDIN H2 SYNTHASE-1 COMPLEX.png
|width=
|width=
|HGNCid=9604
|HGNCid=9604
|Symbol=[[PTGS1]]
|Symbol=[[PTGS1]]
|AltSymbols=
|AltSymbols=COX-1
|EntrezGene=5742
|EntrezGene=5742
|OMIM=176805
|OMIM=176805
|RefSeq=NM_080591
|RefSeq=NM_080591
|UniProt=P23219
|UniProt=P23219
|PDB=
|PDB=1CQE
|ECnumber=1.14.99.1
|ECnumber=1.14.99.1
|Chromosome=9
|Chromosome=9
Line 18: Line 29:
|LocusSupplementaryData=-q33.3
|LocusSupplementaryData=-q33.3
}}
}}
{{protein
{{infobox protein
|Name=[[PTGS2|prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)]]
|Name=[[PTGS2|cyclooxygenase 2]]
|caption=
|caption= Cyclooxygenase-2 (Prostaglandin Synthase-2) in complex with a COX-2 selective inhibitor.<ref name="pmid8967954">{{PDB|6COX}}; {{cite journal | vauthors = Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC | title = Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents | journal = Nature | volume = 384 | issue = 6610 | pages = 644–8 | year = 1996 | pmid = 8967954 | doi = 10.1038/384644a0 }}</ref>
|image=
|image=Cyclooxygenase-2.png
|width=
|width=
|HGNCid=9605
|HGNCid=9605
|Symbol=[[PTGS2]]
|Symbol=[[PTGS2]]
|AltSymbols=
|AltSymbols=COX-2
|EntrezGene=5743
|EntrezGene=5743
|OMIM=600262
|OMIM=600262
|RefSeq=NM_000963
|RefSeq=NM_000963
|UniProt=P35354
|UniProt=P35354
|PDB=
|PDB=6COX
|ECnumber=1.14.99.1
|ECnumber=1.14.99.1
|Chromosome=1
|Chromosome=1
Line 37: Line 48:
|LocusSupplementaryData=-25.3
|LocusSupplementaryData=-25.3
}}
}}
{{CMG}} 


'''Associate Editor:''' {{CZ}}
'''Cyclooxygenase''' ('''COX'''), officially known as '''prostaglandin-endoperoxide synthase''' (PTGS), is an [[enzyme]] (specifically, a family of [[isozyme]]s, {{EC_number|1.14.99.1}}) that is responsible for formation of [[prostanoid]]s, including [[thromboxane]] and [[prostaglandin]]s such as [[prostacyclin]].
 
[[Pharmaceutical drug|Pharmaceutical]] inhibition of ''COX'' can provide relief from the symptoms of [[inflammation]] and [[pain]]. [[Nonsteroidal anti-inflammatory drug]]s (NSAIDs), such as [[aspirin]] and [[ibuprofen]], exert their effects through inhibition of COX. Those that are specific to the COX-2 isozyme are called [[COX-2 inhibitor]]s. The active metabolite of Paracetamol believed to provide most or all of its analgesic effects [[AM404]] is a COX inhibitor and this is believed to provide part of its effect.<ref name="pmid15987694">{{cite journal |vauthors=Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM | title = Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system | journal = J. Biol. Chem. | volume = 280 | issue = 36 | pages = 31405–12 |date=September 2005 | pmid = 15987694 | doi = 10.1074/jbc.M501489200 | url = http://www.jbc.org/content/280/36/31405.full.pdf | format = pdf }}</ref>
 
In [[medicine]], the [[gene nomenclature#Symbol and name|root symbol]] "COX" is encountered more often than "PTGS". In [[genetics]], "PTGS" is officially used for this family of [[gene]]s and [[protein]]s, because the root symbol "COX" was already used for the [[cytochrome c oxidase]] family. Thus the two isozymes found in humans, [[PTGS1]] and [[PTGS2]], are frequently called COX-1 and COX-2 in the [[medical literature]]. The names "prostaglandin synthase (PHS)", "prostaglandin synthetase (PHS)", and "prostaglandin-endoperoxide synthetase (PES)" are older terms still sometimes used to refer to COX.
 
== Pharmacology ==


In terms of their molecular biology, ''COX-1'' and ''COX-2'' are of similar molecular weight, approximately 70 and 72 k[[dalton (unit)|Da]], respectively, and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of [[isoleucine]] at position 523 in ''COX-1'' with [[valine]] in ''COX-2''. The smaller Val<sub>523</sub> residue in ''COX-2'' allows access to a [[hydrophobic]] side-pocket in the enzyme (which Ile<sub>523</sub> sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of ''COX-2''.


=== Classical NSAIDs ===


==Definition==
{{See also|Mechanism of action of aspirin}}
'''Cyclooxygenase''' ('''COX''') is an [[enzyme]] ({{EC_number|1.14.99.1}}) that is responsible for formation of important biological mediators called [[prostanoid]]s (including [[prostaglandin]]s, [[prostacyclin]] and [[thromboxane]]). Pharmacological inhibition of ''COX'' can provide relief from the symptoms of [[inflammation]] and [[Pain and nociception|pain]]; this is the method of action of well-known drugs such as [[aspirin]] and [[ibuprofen]].
The main ''COX'' inhibitors are the [[non-steroidal anti-inflammatory drug]]s (NSAIDs).


== Physiology ==
The classical ''COX'' inhibitors are not selective and inhibit all types of ''COX''. The resulting inhibition of [[prostaglandin]] and [[thromboxane]] synthesis has the effect of reduced inflammation, as well as antipyretic, antithrombotic and analgesic effects. The most frequent adverse effect of NSAIDs is irritation of the gastric mucosa as [[prostaglandin]]s normally have a protective role in the gastrointestinal tract. Some NSAIDs are also acidic which may cause additional damage to the gastrointestinal tract.
''See also [[prostaglandin]] and [[eicosanoid]] for more details''


''COX'' converts [[arachidonic acid]] (AA, an [[Omega-6 fatty acid|ω-6]] PUFA) to [[prostaglandin|prostaglandin H<sub>2</sub>]] (PGH<sub>2</sub>), the precursor of the series-2 [[prostanoid]]s. The enzyme contains two active sites: a [[heme]] with [[peroxidase]] activity, responsible for the reduction of PGG<sub>2</sub> to PGH<sub>2</sub>, and a  cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G<sub>2</sub> (PGG<sub>2</sub>). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the [[peroxidase]] active site. Two O<sub>2</sub> molecules then react with the arachidonic acid radical, yielding PGG<sub>2</sub>.
=== Newer NSAIDs ===


Currently three ''COX'' isoenzymes are known&mdash;''[[PTGS1|COX-1]]'', ''[[COX-2]]'' and ''[[PTGS1|COX-3]]''. ''COX-3'' is a [[Splicing (genetics)|splice variant]] of COX-1 which retains [[intron]] one and has a [[frameshift mutation]], thus some prefer the name ''COX-1b'' or ''COX-1 variant'' (''COX-1v'').<ref>Chandrasekharan, N.V., Dai, H., Roos, K.L.T. et al. 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 of the United States of America 99(21):13926-31, (2002). PMID 12242329.</ref>
Selectivity for ''COX-2'' is the main feature of [[celecoxib]], [[etoricoxib]], and other members of this drug class.  Because COX-2 is usually specific to inflamed tissue, there is much less gastric irritation associated with COX-2 inhibitors, with a decreased risk of peptic ulceration. The selectivity of COX-2 does not seem to negate other side-effects of NSAIDs, most notably an increased risk of [[renal failure]], and there is evidence that indicates an increase in the risk of [[myocardial infarction|heart attack]], [[thrombosis]], and [[stroke]] through an increase of [[thromboxane]] unbalanced by prostacyclin (which is reduced by COX-2 inhibition). {{Citation needed|date=March 2013}} [[Rofecoxib]] (brand name [[Vioxx]]) was withdrawn in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such as [[celecoxib]], and [[etoricoxib]], are still on the market.


Different tissues express varying levels of ''COX-1'' and ''[[COX-2]]''. Although both enzymes act basically in the same fashion, selective inhibition can make a difference in terms of side-effects. ''COX-1'' is considered a constitutive enzyme, being found in most mammalian cells. More recently it has been shown to be upregulated in various carcinomas and to have a central role in tumorigenesis. ''[[COX-2]]'', on the other hand, is undetectable in most normal tissues. It is an [[adaptive enzyme|inducible enzyme]], becoming abundant in activated [[macrophage]]s and other cells at sites of inflammation.
=== Natural COX inhibition ===


Both COX-1 and COX-2 also oxygenate two other essential fatty acids &ndash; [[Dihomo-gamma-linolenic acid|DGLA]] (ω-6) and [[Eicosapentaenoic acid|EPA]] (ω-3) &ndash; to give the series-1 and series-3 prostanoids, which are less [[inflammation|inflammatory]] than those of series-2.  DGLA and EPA are competitive inhibitors with AA for the COX pathways.  This inhibition is a major mode of action in the way that dietary sources of DGLA and EPA (e.g. borage, [[fish oil]]) reduce inflammation.
Culinary mushrooms, like [[maitake]], may be able to partially inhibit COX-1 and COX-2.<ref name="pmid12475274">{{cite journal | vauthors = Zhang Y, Mills GL, Nair MG | title = Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa | journal = Journal of Agricultural and Food Chemistry | volume = 50 | issue = 26 | pages = 7581–5 | date = Dec 2002 | pmid = 12475274 | doi = 10.1021/jf0257648 }}</ref><ref name="pmid12834003">{{cite journal | vauthors = Zhang Y, Mills GL, Nair MG | title = Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita | journal = Phytomedicine | volume = 10 | issue = 5 | pages = 386–90 | year = 2003 | pmid = 12834003 | doi = 10.1078/0944-7113-00272 }}</ref>
[[Image:Cyclooxygenase (COX).JPG|thumb|200px|Enzyme cyclooxygenase (box: first step in creating prostaglandins from fatty acids) ([http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb17_1.html more details...])]]
[[Image: cycloxygenase.gif|thumb|200px|Cyclooxygenase reaction mechanism]]


== Pharmacology ==
A variety of [[flavonoid]]s have been found to inhibit COX-2.<ref name="pmid15225597">{{cite journal | vauthors = O'Leary KA, de Pascual-Teresa S, de Pascual-Tereasa S, Needs PW, Bao YP, O'Brien NM, Williamson G | title = Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription | journal = Mutation Research | volume = 551 | issue = 1-2 | pages = 245–54 | date = Jul 2004 | pmid = 15225597 | doi = 10.1016/j.mrfmmm.2004.01.015 }}</ref>
In terms of their molecular biology, ''COX-1'' and ''[[COX-2]]'' are of similar molecular weight (approximately 70 and 72 kdalton (kDa) respectively), and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of [[isoleucine]] at position 523 in ''COX-1'' with [[valine]] in ''[[COX-2]]''. The relatively smaller Val<sub>523</sub> residue in ''[[COX-2]]'' allows access to a [[hydrophobic]] side-pocket in the enzyme (which Ile<sub>523</sub> sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of ''[[COX-2]]''.


=== Classical NSAIDs ===
[[Fish oils]] provide alternative fatty acids to arachidonic acid. These acids can be turned into some anti-inflammatory prostacyclins by COX instead of pro-inflammatory prostaglandins.<ref name="fish_oils">{{cite journal | vauthors = Cleland LG, James MJ, Proudman SM | title = Fish oil: what the prescriber needs to know | journal = Arthritis Research & Therapy | volume = 8 | issue = 1 | pages = 202 | year = 2006 | pmid = 16542466 | pmc = 1526555 | doi = 10.1186/ar1876 }}</ref>
The main ''COX'' inhibitors are the [[non-steroidal anti-inflammatory drug]]s (NSAIDs).


The classical ''COX'' inhibitors are not selective (i.e. they inhibit all types of ''COX''), and the main adverse effects of their use are [[peptic ulcer]]ation and [[dyspepsia]]. It is believed that this may be due to the "dual-insult" of NSAIDs - direct irritation of the gastric mucosa (many NSAIDs are acids), and inhibition of [[prostaglandin]] synthesis by ''COX-1''. Prostaglandins have a protective role in the gastrointestinal tract, preventing acid-insult to the mucosa.
[[Hyperforin]] has been shown to inhibit COX-1 around 3-18 times as much as aspirin.<ref>{{cite journal | vauthors = Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O | title = Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase | journal = Biochemical Pharmacology | volume = 64 | issue = 12 | pages = 1767–75 | date = Dec 2002 | pmid = 12445866 | doi=10.1016/s0006-2952(02)01387-4}}</ref>


=== Newer NSAIDs ===
[[Calcitriol]] ([[vitamin D]]) significantly inhibits the expression of the COX-2 gene.<ref name="pmid16886660">{{cite journal | vauthors = Moreno J, Krishnan AV, Peehl DM, Feldman D | title = Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway | journal = Anticancer Research | volume = 26 | issue = 4A | pages = 2525–30 | date = July–August 2006 | pmid = 16886660 | doi =  | url = http://ar.iiarjournals.org/content/26/4A/2525.abstract }}</ref>
Selectivity for ''[[COX-2]]'' is the main feature of [[celecoxib]], [[rofecoxib]] and other members of this drug class, but these drugs carry the risk of peptic ulceration. [[COX-2]]-selectivity does not seem to affect other side-effects of NSAIDs (most notably an increased risk of [[renal failure]]), and some results have aroused the suspicion that there might be an increase in the risk for [[myocardial infarction|heart attack]], [[thrombosis]] and [[stroke]] by a relative increase in [[thromboxane]]. [[Rofecoxib]] (brand name [[Vioxx]]) was taken off the market in 2004 because of these concerns. Some other [[COX-2]] selective NSAIDs, such as [[celecoxib]] and [[etoricoxib]], are still on the market.


=== Non-NSAID COX inhibition ===
Caution should be exercised in combining low dose aspirin with COX-2 inhibitors due to potential increased damage to the gastric mucosa.  COX-2 is upregulated when COX-1 is suppressed with aspirin, which is thought to be important in enhancing mucosal defense mechanisms and lessening the erosion by aspirin.<ref>{{cite journal | vauthors = Wallace JL | title = Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? | journal = Physiological Reviews | volume = 88 | issue = 4 | pages = 1547–65 | date = Oct 2008 | pmid = 18923189 | doi = 10.1152/physrev.00004.2008 | url = http://physrev.physiology.org/content/88/4/1547.long }}</ref>
It has been suggested that [[acetaminophen]], also known as paracetamol, reversibly inhibits ''COX-3'', although there is now some doubt about this theory.  ''COX-3''  produces prostanoids in the brain, but does not participate in eicosanoid signalling in inflammation.  Acetaminophen thereby  may interfere with  the perception of pain.  Since it has no effect on inflammation, it is not classed as an NSAID.<ref>{{cite journal
  |title= Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?
  | author= Warner, Timothy D. and Mitchell, Jane A.
  | url=http://www.pnas.org/cgi/content/extract/99/21/13371
  | year = October 8, 2002 | doi= 10.1073/pnas.222543099
  | journal =PNAS  | volume= 99 | issue=21 | pages=13371-13373
  | accessdate = 2007-01-05}} </ref><ref> {{cite journal | journal =J. Clin. Invest| volume= 111 |pages=1107-1113 |year=2003
  | url = http://www.jci.org/cgi/content/full/111/8/1107
  |doi = doi:10.1172/JCI200318338
  |title =The organization and consequences of eicosanoid signaling
  |author = Soberman, Roy J.  and Christmas, Peter
  |accessdate = 2007-01-05}}</ref>


=== Cardiovascular side effects of COX inhibitors ===
=== Cardiovascular side-effects of COX inhibitors ===
''[[COX-2]]'' inhibitors have been found to increase the risk of [[Thrombosis|atherothrombosis]] even with short term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants <ref>Kearney PM, Baigent C, Godwin J, Halls H, et al. ''Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.'' BMJ. 2006 Jun 3;332(7553):1302-8. PMID 16740558</ref>
showed that selective ''[[COX-2]]'' inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of [[myocardial infarction]], and also that high dose regimens of some traditional NSAIDs such as [[diclofenac]] and [[ibuprofen]] are associated with a similar increase in risk of vascular events.


== References ==
COX-2 inhibitors have been found to increase the risk of [[Thrombosis|atherothrombosis]] even with short-term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants<ref name="pmid16740558">{{cite journal | vauthors = Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C | title = Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials | journal = BMJ | volume = 332 | issue = 7553 | pages = 1302–8 | date = Jun 2006 | pmid = 16740558 | pmc = 1473048 | doi = 10.1136/bmj.332.7553.1302 }}</ref> showed that selective ''COX-2'' inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of [[myocardial infarction]], and also that high-dose regimens of some traditional NSAIDs (such as [[diclofenac]] and [[ibuprofen]], but not [[naproxen]]) are associated with a similar increase in risk of vascular events.
{{reflist|2}}


==Further reading==
Fish oils (e.g., [[cod liver oil]]) have been proposed as a reasonable alternative for the treatment of [[rheumatoid arthritis]] and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs.<ref name='fish_oils'/>
*Pedro J. Silva, Pedro A. Fernandes and Maria J. Ramos (2003) A theoretical study of radical-only and combined radical/carbocationic mechanisms of arachidonic acid cyclooxygenation by prostaglandin H synthase. [http://dx.doi.org/10.1007/s00214-003-0476-9  Theoretical Chemistry Accounts, 110, 345-351.]


== See also ==
== See also ==
* [[Arachidonic acid]]
* [[PTGS1|Cyclooxygenase 1]]
* [[Prostaglandin-endoperoxide synthase 2|Cyclooxygenase 2]]
* [[NSAID]]
* [[Discovery and development of cyclooxygenase 2 inhibitors|Discovery and development of COX-2 selective inhibitors]]
* [[COX-2 selective inhibitor]]
* [[COX-2 selective inhibitor]]
* [[PTGS2]]
* [[COX-3]] (not functional in humans)
 
== References ==
{{reflist|33em}}


==External links==
== External links ==
* [http://macromoleculeinsights.com/cox.php The Cyclooxygenase Protein]
* [http://macromoleculeinsights.com/cox.php The Cyclooxygenase Protein]
* {{MeshName|Cyclooxygenase}}
* {{MeshName|Cyclooxygenase}}
* [http://gowiki.tamu.edu/wiki/index.php/cyclooxygenase GONUTS Page: Cyclooxygenase]
* [http://proteopedia.org/wiki/index.php/Cyclooxygenase Cyclooxygenase: Proteopedia, life in 3D]
* [http://homepage.ufp.pt/pedros/science/cox/cox.htm: A discussion of the enzymatic mechanism, including interactive 3D models]{{dead link|date=August 2017 |bot=InternetArchiveBot |fix-attempted=yes }}


{{Oxygenases}}
{{Metabolism of complex lipids}}
{{Lipid metabolism enzymes}}
{{Prostanoidergics}}
 
{{Dioxygenases}}
[[Category:Pharmacology]]
{{Enzymes}}
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Revision as of 22:15, 21 September 2017

"COX" redirects here. For other uses, see Cox (disambiguation).
prostaglandin-endoperoxide synthase
Identifiers
EC number1.14.99.1
CAS number9055-65-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
cyclooxygenase 1
File:PROSTAGLANDIN H2 SYNTHASE-1 COMPLEX.png
Crystallographic structure of prostaglandin H2 synthase-1 complex with flurbiprofen.[1]
Identifiers
SymbolPTGS1
Alt. symbolsCOX-1
Entrez5742
HUGO9604
OMIM176805
PDB1CQE
RefSeqNM_080591
UniProtP23219
Other data
EC number1.14.99.1
LocusChr. 9 q32-q33.3
cyclooxygenase 2
File:Cyclooxygenase-2.png
Cyclooxygenase-2 (Prostaglandin Synthase-2) in complex with a COX-2 selective inhibitor.[2]
Identifiers
SymbolPTGS2
Alt. symbolsCOX-2
Entrez5743
HUGO9605
OMIM600262
PDB6COX
RefSeqNM_000963
UniProtP35354
Other data
EC number1.14.99.1
LocusChr. 1 q25.2-25.3

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, EC 1.14.99.1) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin.

Pharmaceutical inhibition of COX can provide relief from the symptoms of inflammation and pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, exert their effects through inhibition of COX. Those that are specific to the COX-2 isozyme are called COX-2 inhibitors. The active metabolite of Paracetamol believed to provide most or all of its analgesic effects AM404 is a COX inhibitor and this is believed to provide part of its effect.[3]

In medicine, the root symbol "COX" is encountered more often than "PTGS". In genetics, "PTGS" is officially used for this family of genes and proteins, because the root symbol "COX" was already used for the cytochrome c oxidase family. Thus the two isozymes found in humans, PTGS1 and PTGS2, are frequently called COX-1 and COX-2 in the medical literature. The names "prostaglandin synthase (PHS)", "prostaglandin synthetase (PHS)", and "prostaglandin-endoperoxide synthetase (PES)" are older terms still sometimes used to refer to COX.

Pharmacology

In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight, approximately 70 and 72 kDa, respectively, and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The smaller Val523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile523 sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2.

Classical NSAIDs

See also: Mechanism of action of aspirin

The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs).

The classical COX inhibitors are not selective and inhibit all types of COX. The resulting inhibition of prostaglandin and thromboxane synthesis has the effect of reduced inflammation, as well as antipyretic, antithrombotic and analgesic effects. The most frequent adverse effect of NSAIDs is irritation of the gastric mucosa as prostaglandins normally have a protective role in the gastrointestinal tract. Some NSAIDs are also acidic which may cause additional damage to the gastrointestinal tract.

Newer NSAIDs

Selectivity for COX-2 is the main feature of celecoxib, etoricoxib, and other members of this drug class. Because COX-2 is usually specific to inflamed tissue, there is much less gastric irritation associated with COX-2 inhibitors, with a decreased risk of peptic ulceration. The selectivity of COX-2 does not seem to negate other side-effects of NSAIDs, most notably an increased risk of renal failure, and there is evidence that indicates an increase in the risk of heart attack, thrombosis, and stroke through an increase of thromboxane unbalanced by prostacyclin (which is reduced by COX-2 inhibition).[citation needed] Rofecoxib (brand name Vioxx) was withdrawn in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such as celecoxib, and etoricoxib, are still on the market.

Natural COX inhibition

Culinary mushrooms, like maitake, may be able to partially inhibit COX-1 and COX-2.[4][5]

A variety of flavonoids have been found to inhibit COX-2.[6]

Fish oils provide alternative fatty acids to arachidonic acid. These acids can be turned into some anti-inflammatory prostacyclins by COX instead of pro-inflammatory prostaglandins.[7]

Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.[8]

Calcitriol (vitamin D) significantly inhibits the expression of the COX-2 gene.[9]

Caution should be exercised in combining low dose aspirin with COX-2 inhibitors due to potential increased damage to the gastric mucosa. COX-2 is upregulated when COX-1 is suppressed with aspirin, which is thought to be important in enhancing mucosal defense mechanisms and lessening the erosion by aspirin.[10]

Cardiovascular side-effects of COX inhibitors

COX-2 inhibitors have been found to increase the risk of atherothrombosis even with short-term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants[11] showed that selective COX-2 inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of myocardial infarction, and also that high-dose regimens of some traditional NSAIDs (such as diclofenac and ibuprofen, but not naproxen) are associated with a similar increase in risk of vascular events.

Fish oils (e.g., cod liver oil) have been proposed as a reasonable alternative for the treatment of rheumatoid arthritis and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs.[7]

See also

References

  1. ↑ PDB: 1CQE​; Picot D, Loll PJ, Garavito RM (Jan 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature. 367 (6460): 243–9. doi:10.1038/367243a0. PMID 8121489.
  2. ↑ PDB: 6COX​; Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996). "Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents". Nature. 384 (6610): 644–8. doi:10.1038/384644a0. PMID 8967954.
  3. ↑ Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (September 2005). "Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system" (pdf). J. Biol. Chem. 280 (36): 31405–12. doi:10.1074/jbc.M501489200. PMID 15987694.
  4. ↑ Zhang Y, Mills GL, Nair MG (Dec 2002). "Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa". Journal of Agricultural and Food Chemistry. 50 (26): 7581–5. doi:10.1021/jf0257648. PMID 12475274.
  5. ↑ Zhang Y, Mills GL, Nair MG (2003). "Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita". Phytomedicine. 10 (5): 386–90. doi:10.1078/0944-7113-00272. PMID 12834003.
  6. ↑ O'Leary KA, de Pascual-Teresa S, de Pascual-Tereasa S, Needs PW, Bao YP, O'Brien NM, Williamson G (Jul 2004). "Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription". Mutation Research. 551 (1–2): 245–54. doi:10.1016/j.mrfmmm.2004.01.015. PMID 15225597.
  7. ↑ 7.0 7.1 Cleland LG, James MJ, Proudman SM (2006). "Fish oil: what the prescriber needs to know". Arthritis Research & Therapy. 8 (1): 202. doi:10.1186/ar1876. PMC 1526555. PMID 16542466.
  8. ↑ Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O (Dec 2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology. 64 (12): 1767–75. doi:10.1016/s0006-2952(02)01387-4. PMID 12445866.
  9. ↑ Moreno J, Krishnan AV, Peehl DM, Feldman D (July–August 2006). "Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway". Anticancer Research. 26 (4A): 2525–30. PMID 16886660.
  10. ↑ Wallace JL (Oct 2008). "Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?". Physiological Reviews. 88 (4): 1547–65. doi:10.1152/physrev.00004.2008. PMID 18923189.
  11. ↑ Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (Jun 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials". BMJ. 332 (7553): 1302–8. doi:10.1136/bmj.332.7553.1302. PMC 1473048. PMID 16740558.

External links

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