Aspirin biosynthesis

Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. Br Med J 1975 1 67-69. 

The antipyretic and analgesic actions of aspirin are believed to occur in a certain area of the brain. It is also thought by some that the salicylates exert their analgesia by their effect on water balance. Aspirin is anti-inflammatory because it inhibits the biosynthesis of chemicals called prostaglandins. The irritation of the stomach lining caused by aspirin can be alleviated with the use of mild bases such as sodium bicarbonate, aluminum glycinate, sodium citrate, aluminum hydroxide, or magnesium trisilicate (a common trademark for this type of aspirin is Bufferin ). 

The NSAIDs (eg, indomethacin, ibuprofen see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition ofTXA2 biosynthesis. 

Aspirin has been used to treat arthritis for approximately 100 years, but its mechanism of action—inhibition of COX activity—was not discovered until 1971. COX-2 appears to be the form of the enzyme most associated with cells involved in the inflammatory process although, as outlined above, COX-1 also contributes significantly to prostaglandin biosynthesis during inflammation. 

The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins (Figure 36-2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COX-selective NSAIDs are reversible inhibitors. 

Acetylsalicyclic acid, aspirin, inhibits the cyclooxygenase-catalyzed first step in the biosynthesis of prostaglandins, prostacyclins and thromboxanes. These latter substances are responsible for the inflammatory and pyretic effects of infection. It is believed that the chemical inhibition reaction involves the acetylation of the enzyme by the aspirin. 

Carboxylic acids, compounds of the type RCOH, constitute one of the most frequently encountered classes of organic compounds. Countless natural products are carboxylic acids or are derived from them. Some carboxylic acids, such as acetic acid, have been known for centuries. Others, such as the prostaglandins, which are powerful regulators of numerous biological processes, remained unknown until relatively recently. Still others, aspirin for example, are the products of chemical synthesis. The therapeutic effects of aspirin, welcomed long before the discovery of prostaglandins, are now understood to result from aspirin s ability to inhibit the biosynthesis of prostaglandins. 

Vane discovered that aspirin blocks the biosynthesis of prostaglandins. 

As discussed previously, aspirin inhibits platelet-induced thrombus formation through its ability to inhibit thromboxane biosynthesis. Aspirin has therefore been used to help prevent the onset or recurrence of heart attacks in some individuals by inhibiting thrombus formation in the coronary arteries.97,109 Similarly, daily aspirin use may help prevent transient ischemic attacks and stroke by preventing cerebral infarction in certain patients.97,109 The role of aspirin in treating coagulation disorders is discussed in more detail in Chapter 25... 

The NSAIDs (eg, aspirin, indomethacin, ibuprofen) block both prostaglandin and thromboxane formation by inhibiting COX activity. For example, aspirin is a long-lasting inhibitor of platelet COX and of TXA2 biosynthesis because it irreversibly acetylates the enzyme. Once acetylated, platelet COX cannot be restored via protein biosynthesis because platelets lack a nucleus. 

Eikelboom JW Hirsh J, Weitz Jl, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002 105 1650-1655. 

Prostaglandin (PG) H Synthase. The enzyme PGH synthase is a homodimeric protein consisting of subunits with an approximate molecular weight of 72 kDa and one Fe(III)-protoporphyrin IX (PPIXFe(III)) prosthetic group per subunit. This protein is responsible for the central reaction in the biosynthesis of prostaglandins and is selectively inhibited by antiinflammatory drugs such as aspirin and indo-... 

Studying the biosynthesis of eicosanoids has led to other discoveries as well. For example, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inactivate the cyclooxygenase enzyme needed for prostaglandin synthesis. In this way, NSAIDs block the synthesis of the prostaglandins that cause inflammation (Section 19.6). 

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