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Cyclooxygenase (COX) is an enzyme (EC 1.14.99.1) that is responsible for formation of important biological mediators called prostanoids (including prostaglandins, prostacyclin and thromboxane). Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain; this is the method of action of well-known drugs such as aspirin and ibuprofen.

See also prostaglandin and eicosanoid for more details

COX converts arachidonic acid (AA, an ω-6 PUFA) to prostaglandin H₂ (PGH₂), the precursor of the series-2 prostanoids. The enzyme contains two active sites: a heme with peroxidase activity, responsible for the reduction of PGG₂ to PGH₂, and a cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G₂ (PGG₂). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the peroxidase active site. Two O₂ molecules then react with the arachidonic acid radical, yielding PGG₂.

Currently three COX isoenzymes are known—COX-1, COX-2 and COX-3. COX-3 is a 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).^[1]

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 inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation.

Both COX-1 and -2 also oxygenate two other essential fatty acids – DGLA (ω-6) and EPA (ω-3) – to give the series-1 and series-3 prostanoids, which are less 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.

Enzyme cyclooxygenase (box: first step in creating prostaglandins from fatty acids) (more details...)

Cyclooxygenase reaction mechanism

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 relatively 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.

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

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 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.

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.^[2][3]

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 ^[4] 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.

• 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. Theoretical Chemistry Accounts, 110, 345-351.

• COX-2 selective inhibitor
• PTGS2

• The Cyclooxygenase Protein
• MeSH Cyclooxygenase