COX-1 and COX-2
Non-steroidal anti-inflammatory drugs (NSAIDs ), such as aspirin and derivatives of ibuprofen, inhibit Cyclooxygenase activity of PGH2 Synthase. They inhibit formation of prostaglandins involved in fever, pain and inflammation. They inhibit blood clotting by blocking thromboxane formation in blood platelets.
Ibuprofen and related compounds act by blocking the hydrophobic channel by which arachidonate enters the Cyclooxygenase active site.
Aspirin acetylates a serine hydroxyl group near the active site, preventing arachidonate binding. The inhibition by aspirin is irreversible. However, in most body cells re-synthesis of PGH2 Synthase would restore cyclooxygenase activity.
Thromboxane A2 stimulates blood platelet aggregation, essential to the role of platelets in blood clotting. Many people take a daily aspirin for its anti-clotting effect, attributed to inhibition of thromboxane formation in blood platelets. This effect of aspirin is long-lived, because platelets lack a nucleus and do not make new enzyme.
Two isoforms of PGH2 Synthase are designated COX-1 and COX-2 (Cyclooxygenase 1 & 2).
COX-1 is constitutively expressed at low levels in many cell types.
COX-2 expression is stimulated by growth factors, cytokines, and endotoxins.
Different localization of these isoforms within a cell, coupled to localization of enzymes that convert the product PGH2 into particular prostaglandins or thromboxanes, may result in COX-1 and COX-2 yielding different ultimate products.
COX-1 is essential for thromboxane formation in blood platelets, and for maintaining integrity of the gastrointestinal epithelium.
Inflammation is associated with up-regulation of COX-2 and increased formation of particular prostaglandins. COX-2 levels increase in inflammatory diseases such as arthritis.
Increased COX-2 expression is seen in some cancer cells. Angiogenesis (blood vessel development), which is essential to tumor growth, requires COX-2. Overexpression of COX-2 leads to increased expression of VEGF (vascular endothelial growth factor). Regular use of NSAIDs has been shown to decrease the risk of developing colorectal cancer.
Most NSAIDs inhibit both COX-1 and COX-2.
Selective COX-2 inhibitors have been developed (e.g., Celebrex and Vioxx).
COX-2 inhibitors are anti-inflammatory & block pain, but are less likely to cause gastric toxicity associated with chronic use of NSAIDs that block COX-1.
A tendency to develop blood clots when taking some of these drugs has been attributed to:
decreased production of an anti-thrombotic (clot blocking) prostaglandin (PGI2) by endothelial cells lining small blood vessels
lack of inhibition of COX-1-mediated formation of pro-thrombotic thromboxanes in platelets.
Although aspirin and NSAIDs inhibit the biosynthetic activity of both COX enzymes, their actions are nonidentical. Aspirin irreversibly inhibits the cyclooxygenase active site of PGHS, but does not affect the peroxidase portion of the enzyme. Interestingly, aspirin does not simply
inhibit COX-2, but rather diverts its enzymatic activity toward the synthesis of precursors of lipoxin A4, a potent antiinflammatory lipid. In contrast, NSAIDs compete with arachidonic acid for the active sites of both COX enzymes. While the active sites of COX-1 and COX-2 are similar in structure, they differ in size. The active site of COX-2 is larger, owing to a replacement of isoleucine-434 of COX-1 with valine-434. The identification of the difference between the active sites permitted the development of COX-2 specific inhibitors, which fit COX-2 but are excluded from COX-1. Despite the difference in size of the active sites, the Km of COX-1 and COX-2 for arachidonic acid remains similar.
Other informations about inhibition of COX-1/2 can be found here and here.
Polipi nasali: glucocorticoidi controllano COX-1
I forti effetti antiinfiammatori dei glucocorticoidi topici sui polipi nasali possono essere in parte dovuti ad un controllo dell'incremento dell'espressione epiteliale di COX-1 che si osserva in questa patologia. L'azione antiinfiammatoria dei glucocorticoidi in questa situazione viene comunemente attribuita alla loro interferenza con la sintesi dei prostanoidi, e sia COX-1 che COX-2 sono implicate in tale sintesi. E' stato ipotizzato che siano gli elevati livelli di COX-1, e non di COX-2, i responsabili per la relativa predominanza dei prostanoidi proinfiammatori nella poliposi nasale. Il trattamento con glucocorticoidi topici d'altro canto non è stato associato ad una riduzione delle cellule COX-2+, ma piuttosto ad un loro aumento. Questo effetto differenziale potrebbe essere dovuto a differenze nelle concentrazioni tissutali di glucocorticoidi topici ed orali, oppure al legame con diversi sottotipi di recettori. (Allergy 2009; 64: 96-103)