Interaction of NSAIDs with cyclooxygenase

The inhibition of COX activity by NSAIDs occurs in two main ways. Most NSAIDs inhibit this enzyme by binding in a reversible manner to a site within the channel through which arachidonic acid must insert to be metabolized (Figure 1). In contrast, aspirin produces an irreversible alteration in the conformation of the active site such that arachidonic acid can no longer gain access. Aspirin produces this effect by acetylating a serine residue in COX. Thus, the recovery of prostanoid synthesis after administration of aspirin is a function of the rate of turnover of COX in each tissue. The irreversible blockade of COX by aspirin accounts for the utility of this drug in the prophylaxis of stroke and myocardial infarction. Due to their reversible binding to COX, most NSAIDs are competitive inhibitors of COX. When plasma levels of the NSAID decline below a critical level, COX activity is restored. On the other hand, COX activity is only restored following aspirin administration through the synthesis of new enzyme. Platelet aggregation is regulated by two key prostanoids. Thromboxane produced by the platelet stimulates aggregation, while prostacyclin produced by the vascular endothelium inhibits platelet aggregation. Following aspirin administration, endothelial prostacyclin synthesis is inhibited until such time as new COX is synthesized (the plasma half-life of aspirin is only -15 min). However, platelets lack the nuclear machinery to synthesize new COX, so aspirin effectively blocks their ability to synthesize thromboxane permanently. Thromboxane synthesis only returns with the appearance of new platelets in the circulation. Thus, giving small doses of aspirin daily leads to marked suppression of thromboxane synthesis with little or no effect on endothelial prostacyclin synthesis, thereby producing a net antithrombotic effect.

In recent years, it has become clear that COX exists in at least two distinct forms. COX-1 is consti-tutively expressed in many tissues, including the stomach, kidney and platelet, and is believed to produce the prostaglandins that mediate important physiological functions in these tissues (Figure 2). On the

Figure 1 Cyclooxygenase metabolizes arachidonic acid to prostaglandins G and H, which are in turn converted to a number of bioactive prostanoids (PGE2, PGI2, TXA2). Arachidonic acid inserts into a channel in COX (panel A) and can then undergo conversion to PGG2/PGH2 (panel B). Most NSAIDs bind to a site within the channel through which arachidonic acid must insert to be metabolized, thereby blocking the activity of COX (panel C). Aspirin acetylates a serine residue in COX resulting in a conformational change in the active site, such that arachidonic acid can not be converted to PGG2/PGH2 (panel D).

Figure 1 Cyclooxygenase metabolizes arachidonic acid to prostaglandins G and H, which are in turn converted to a number of bioactive prostanoids (PGE2, PGI2, TXA2). Arachidonic acid inserts into a channel in COX (panel A) and can then undergo conversion to PGG2/PGH2 (panel B). Most NSAIDs bind to a site within the channel through which arachidonic acid must insert to be metabolized, thereby blocking the activity of COX (panel C). Aspirin acetylates a serine residue in COX resulting in a conformational change in the active site, such that arachidonic acid can not be converted to PGG2/PGH2 (panel D).

other hand, COX-2 is not constitutively expressed in many tissues, but can be induced in many tissues by a number of cytokines and mitogens. NSAIDs currently on the market are nonselective, inhibiting both isoforms of COX. As mentioned above, aspirin is able to produce its inhibitory effects on both COX-1 and COX-2 through acetylation of a serine residue, although the position of this residue differs slightly between the two COX isoforms. COX-2 has also

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