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INTRODUCTION

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Membrane lipids supply the substrate for the synthesis of eicosanoids and platelet-activating factor (PAF). Eicosanoids—arachidonate metabolites, including prostaglandins (PGs), prostacyclin (PGI2), thromboxane A2 (TxA2), leukotrienes (LTs), lipoxins, and hepoxilins—are not stored but are produced, by most cells, when a variety of physical, chemical, and hormonal stimuli activate acyl hydrolases that make arachidonate available. Membrane glycerophosphocholine derivatives can be modified enzymatically to produce PAF. PAF is formed by a smaller number of cell types, principally leukocytes, platelets, and endothelial cells. Eicosanoids and PAF lipids contribute to inflammation, smooth muscle tone, hemostasis, thrombosis, parturition, and gastrointestinal secretion. Several classes of drugs, most notably aspirin, the traditional non-steroidal anti-inflammatory agents (tNSAIDs), and the specific inhibitors of cyclooxygenase-2 (COX-2), such as the coxibs, owe their principal therapeutic effects to blockade of eicosanoid formation. To understand the therapeutic potential of selective inhibitors of eicosanoid synthesis and action, we must first review the synthesis, metabolism, and mechanism of action of eicosanoids and PAF.

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EICOSANOIDS

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History. In 1930, Kurzrok and Lieb, two American gynecologists, observed that strips of uterine myometrium relax or contract when exposed to semen. Subsequently, Goldblatt in England and von Euler in Sweden reported independently on smooth muscle-contracting and vasodepressor activities in seminal fluid and accessory reproductive glands. In 1935, von Euler identified the active material as a lipid-soluble acid, which he named prostaglandin, inferring its origin in the prostatic gland. Samuelsson, Bergström, and their colleagues elucidated the structures of prostaglandin E1 (PGE1) and prostaglandin F1α (PGF1α) in 1962. In 1964, Bergström and coworkers, and van Dorp and associates, independently achieved biosynthesis of PGE2 from arachidonic acid (AA). Discovery of TxA2, PGI2, and the LTs followed. Vane, Smith, and Willis reported that aspirin and NSAIDs act by inhibiting prostaglandin biosynthesis (Vane, 1971). This remarkable period of discovery linked the Nobel Prize of von Euler in 1970 to that of Bergström, Samuelsson, and Vane in 1982.

PGs, LTs, and related compounds are called eicosanoids, from the Greek eikosi ("twenty"). Precursor essential fatty acids contain 20 carbons and three, four, or five double bonds: 8,11,14-eicosatrienoic acid (dihomo-γ-linolenic acid), 5,8,11,14-eicosatetraenoic acid [AA; Figure 33–1], and 5,8,11,14,17-eicosapentaenoic acid (EPA). In humans, AA, the most abundant precursor, is either derived from dietary linoleic acid (9,12-octadecadienoic acid) or ingested directly as a dietary constituent. EPA is a major constituent of oils from fatty fish such as salmon.

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Biosynthesis. Biosynthesis of eicosanoids is limited by the availability of substrate and depends primarily on the release of AA, esterified in the sn-2 domain of cell membrane phospholipids, or other complex lipids, to the eicosanoid-synthesizing enzymes by acyl hydrolases, most notably phospholipase A2 (PLA2). Chemical and physical stimuli activate the Ca2+-dependent translocation of group IVA cytosolic PLA2 (cPLA2), which has a high affinity for ...

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