Cyclooxygenase

Physiology

See also eicosanoid for more details

COX converts 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 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 borage, fish oil) reduce inflammation.    

Pharmacology

In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight (approximately 70 and 72 khydrophobic 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

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.

Newer NSAIDs

Selectivity for COX-2 is the main feature of etoricoxib, are still on the market.

Non-NSAID COX inhibition

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]

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 ^[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 ibuprofen are associated with a similar increase in risk of vascular events.

References

Further reading

• 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.

See also

• COX-2 selective inhibitor
• PTGS2

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