Eicosanoids and Prostaglandins - Part 2: Cyclooxgenase-2-Selective Inhibitors: Translating Pharmacology into Clinical Utility

Milestones in eicosanoid research

In the 1930s, researchers in the United States and Sweden independently reported that compounds found in human semen had smooth muscle contraction and vasopressor properties. From their origin, von Eular called these compounds prostaglandins.(7) The biochemistry of prostaglandins remained elusive for 3 decades, primarily due to their paucity and instability. Elucidation of related biosynthetic pathways by Hamberg and Samuelsson in 1967 led to recognition of an abundance of biologically active compounds.(8) In 1971, Vane showed that aspirin could inhibit the synthesis of prostaglandins.(4) Aspirin is now known to target COX, a prostaglandin synthase responsible for the bicyclic endoperoxidation of fatty acids to prostaglandins. An additional pathway in eicosanoid metabolism was found to be mediated by lipoxygenases, resulting in the elucidation of the leukotriene-related pathways in the 1980s and the lipoxins in the 1990s.(9) Together, the prostaglandins, leukotrienes, lipoxins, and related compounds are known to occupy a crucial role in many biologic processes, giving the eicosanoids prominence in modern pharmacology and medicine.

Prostaglandins in physiology and pathophysiology

Eicosanoids are produced from arachidonic acid (a 20-carbon polyunsaturated fatty acid) after its liberation from the cell membrane by phospholipase in response to diverse stimuli.(10) Arachidonic acid is metabolized to eicosanoids by 2 groups of enzymes: the cyclooxygenases, which produce prostaglandins and thromboxane; and the lipoxygenases, which catalyze leukotriene and lipoxin synthesis. Eicosanoids play a key role in inflammation (Figure 1).(10)

The COX enzyme ultimately catalyzes the formation of prostaglandin (PG) H2 from arachidonic acid. Within the tissues, PGH2 is converted to a series of prostaglandins with a wide spectrum of biologic activities.(11) NSAIDs can inhibit the COX isoenzymes. Three lipoxygenases catalyze the metabolism of arachidonic acid to the leukotrienes through a series of reactions.(10) The lipoxygenases are not inhibited by NSAIDs.

Prostaglandin receptors

Prostaglandins possess diverse biologic activities and are therefore significant in the pathophysiology of a wide array of diseases. The tissue-specific and nonoverlapping properties of prostaglandins reflect the compartmentalized nature of receptors through which they act.(12) Many prostaglandin receptors are G-protein coupled receptors, designated EP, FP, IP, TP, and DP; their cognate ligands are PGE2, PGF2α, PGI2, TXA2, and PGD2, respectively.

In light of the many activities of PGE2, it is not surprising that 4 distinct receptor subtypes (EP1-4) have been found to transmit signals from this molecule. (12) All 8 prostaglandin receptors have been cloned and their physiologic roles explored in receptor knock-out mice. Although there is obvious therapeutic potential in the ability to block specific activities of prostaglandins, the physiologic role of the receptors is only partially characterized, and subtype-selective antagonists remain elusive.

Cronstein BN. Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. Cleve Clin J Med 2002;69:SI13-19.

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