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.

Physiology

See also prostaglandin and eicosanoid for more details

COX is part of the enzyme complex that converts arachidonic acid to prostaglandin H₂ (PGH2), the precursor of all prostanoids. The complex consists of a COX isoenzyme and a peroxidase. Currently three COX isoenzymes are known—COX-1, COX-2 and COX-3.

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. 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.

Pharmacology

In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight (67 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.

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 can halve the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. 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 was taken off the market in 2004 because of these concerns.

See also

• NSAID
• Aspirin
• COX-2 selective inhibitor
• Peptic ulcer