Editing Cyclooxygenase (section)

== Pharmacology ==

COX is a common target for anti-inflammatory drugs.  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.<ref name="pmid8967954"/>

=== Classical NSAIDs ===

{{See also|Mechanism of action of aspirin}}
The main COX inhibitors are the [[non-steroidal anti-inflammatory drug]]s.

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 [[kidney 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).<ref>Kumar, V., Abbas, A. K., & Aster, J. C. (2017). Robbins Basic Pathology (10th ed.). Elsevier - Health Sciences Division.
</ref>  [[Rofecoxib]] (brand name [[Vioxx]]) was withdrawn in 2004 because of such concerns.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.<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 = December 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>

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 = July 2004 | pmid = 15225597 | doi = 10.1016/j.mrfmmm.2004.01.015 }}</ref>

[[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 | doi-access = free }}</ref>

[[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 = December 2002 | pmid = 12445866 | doi = 10.1016/s0006-2952(02)01387-4 }}</ref>

[[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 | url = http://ar.iiarjournals.org/content/26/4A/2525.abstract | access-date = 2013-03-12 | archive-date = 2017-04-25 | archive-url = https://web.archive.org/web/20170425063418/http://ar.iiarjournals.org/content/26/4A/2525.abstract | url-status = live }}</ref>

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 |last=Wallace |first=John L. |date=October 2008 |title=Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? |url=https://pubmed.ncbi.nlm.nih.gov/18923189/ |journal=Physiological Reviews |volume=88 |issue=4 |pages=1547–1565 |doi=10.1152/physrev.00004.2008 |issn=0031-9333 |pmid=18923189}}</ref>

=== 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 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 = June 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.

This evidence, however, has been contradicted by the 2016 PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) trial<ref name="pmid27959716">{{cite journal | vauthors = Nissen SE, Yeomans ND, Solomon DH, Luscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE, Qiuqing W, Menon V, Ruschitzka F, Gaffney M, Beckerman B, Berger MF, Weihang B, Lincoff AM | title = Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis | journal = NEJM | volume = 375 | issue = 26 | date = December 2016 | pmid = 27959716 | doi = 10.1056/NEJMoa1611593 }}</ref> of 24,081 participants, which shows a lower incidence of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke for Celecoxib as compared to both Naproxen and Ibuprofen.

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'/>

=== Effects of COX on the immune system ===
Inhibition of COX-2 using celecoxib has been shown to reduce the immunosuppressive TGFβ expression in hepatocytes attenuating EMT in human hepatocellular carcinoma<ref name="pmid22097969">{{cite journal | vauthors = Ogunwobi OO, Wang T, Zhang L, Liu C | title = Cyclooxygenase-2 and Akt mediate multiple growth-factor-induced epithelial-mesenchymal transition in human hepatocellular carcinoma | journal = Journal of Gastroenterology and Hepatology | volume = 27 | issue = 3 | pages = 566–78 | date = March 2012 | pmid = 22097969 | pmc = 3288221 | doi = 10.1111/j.1440-1746.2011.06980.x }}</ref>