Cyclooxygenase
Cyclooxygenase (COX) is an enzyme that is responsible for formation of important biological mediators called prostanoids (including prostaglandins, prostacyclin and thromboxane). Pharmacological inhibition of cox can provide relief of the symptoms of inflammation and pain.
Physiology
- See 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. There are two cox isoenzymes—cox-1 and cox-2.
Pharmacology
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.
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 substition 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 main representatives of which are aspirin, diclofenac and ibuprofen.
The classical cox inhibitors are not selective, 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 non-significant results have aroused the suspicion that there might be an increase in the risk for myocardial infarction and thrombosis by a relative increase in thromboxane.
See also
