Synthesis inhibition refers to the inhibition of the production of prostaglandins (PG) and thromboxanes (TX) by certain compounds. For instance, cortisol, a steroidal anti-inflammatory agent, inhibits the activity of phospholipase A2, preventing the release of arachidonic acid from membrane phospholipids, which is necessary for the synthesis of PG and TX. Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin, indomethacin, and phenylbutazone inhibit both COX-1 and COX-2, thereby preventing the synthesis of the precursor molecule PGH2. Aspirin, unlike other NSAIDs, also induces the synthesis of anti-inflammatory mediators such as lipoxins and inflammation-resolving mediators like resolvins and protectins. Specific inhibitors of COX-2, known as coxibs, were developed to target pathologic inflammatory processes mediated by COX-2 while preserving the physiological functions of COX-1. However, their use has been associated with an increased risk of heart attacks due to decreased synthesis of PGI2. Thromboxane A2 (TXA2) produced by COX-1 in activated platelets promotes platelet adhesion and aggregation, as well as contraction of vascular smooth muscle, leading to the formation of blood clots. On the other hand, prostacyclin (PGI2) produced by COX-2 in vascular endothelial cells inhibits platelet aggregation, stimulates vasodilation, and impedes thrombogenesis. Aspirin exhibits an antithrombogenic effect by inhibiting the synthesis of TXA2 by COX-1 in platelets and PGI2 by COX-2 in endothelial cells through irreversible acetylation of these isozymes. The synthesis of leukotrienes (LT), which are mediators of allergic response and inflammation, involves the conversion of arachidonic acid to hydroperoxy acids by lipoxygenases (LOX), particularly 5-LOX. These hydroperoxy acids are then converted to various LT molecules with different double bond configurations. Inhibitors of 5-LOX and LT-receptor antagonists are used in the treatment of asthma. It's important to note that the synthesis of LT is inhibited by cortisol and not by NSAIDs. However, some individuals with asthma may experience a response to overproduction of LT when using NSAIDs, known as aspirin-exacerbated respiratory disease.
Synthesis inhibition: The synthesis of PG and TX can be inhibited by unrelated compounds. For example, cortisol (a steroidal anti-inflammatory agent) inhibits phospholipase A2 activity (see Fig. 17.23) and, therefore, arachidonic acid, the substrate for PG and TX synthesis, is not released from membrane phospholipids. Aspirin, indomethacin, and phenylbutazone (all nonsteroidal anti-inflammatory drugs [NSAID]) inhibit both COX-1 and COX-2 and, thus, prevent the synthesis of the parent molecule, PGH2. [Note: Systemic inhibition of COX-1, with subsequent damage to the stomach and the kidneys and impaired clotting of blood, is the basis of aspirin’s toxicity.] Aspirin (but not other NSAID) also induces synthesis of lipoxins (anti-inflammatory mediators made from arachidonic acid) and resolvins and protectins (inflammationresolving mediators made from EPA). Inhibitors specific for COX-2 (the coxibs, for example, celecoxib) were designed to reduce pathologic inflammatory processes mediated by COX-2 while maintaining the physiologic functions of COX-1. However, their use has been associated with increased risk of heart attacks, likely as a result of decreased PGI2 synthesis (see B. below), and some have been withdrawn from the market.
B. Thromboxanes and prostaglandins in platelet homeostasis
Thromboxane A2 (TXA2) is produced by COX-1 in activated platelets. It promotes platelet adhesion and aggregation and contraction of vascular smooth muscle, thereby promoting formation of blood clots (thrombi). (See online Chapter 35.) Prostacyclin (PGI2), produced by COX-2 in vascular endothelial cells, inhibits platelet aggregation and stimulates vasodilation and, so, impedes thrombogenesis. The opposing effects of TXA2 and PGI2 limit thrombi formation to sites of vascular injury. [Note: Aspirin has an antithrombogenic effect. It inhibits TXA2 synthesis by COX-1 in platelets and PGI2 synthesis by COX-2 in endothelial cells through irreversible acetylation of these isozymes (Fig. 17.24). COX-1 inhibition cannot be overcome in platelets, which lack nuclei. However, COX-2 inhibition can be overcome in endothelial cells because they have a nucleus and, therefore, can generate more of the enzyme. This difference is the basis of low-dose aspirin therapy used to lower the risk of stroke and heart attacks by decreasing formation of thrombi.]
C. Leukotriene synthesis
Arachidonic acid is converted to a variety of linear hydroperoxy (–OOH) acids by a separate pathway involving a family of lipoxygenases (LOX). For example, 5-LOX converts arachidonic acid to 5-hydroperoxy-6,8,11,14 eicosatetraenoic acid ([5-HPETE]; see Fig. 17.23). 5-HPETE is converted to a series of LT containing four double bonds, the nature of the final products varying according to the tissue. LT are mediators of allergic response and inflammation. Inhibitors of 5-LOX and LT-receptor antagonists are used in the treatment of asthma. [Note: LT synthesis is inhibited by cortisol and not by NSAID. Aspirin-exacerbated respiratory disease is a response to LT overproduction with NSAID use in ~10% of individuals with asthma.]
IX. CHAPTER SUMMARY