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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 nonsteroidal 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.


PGs, LTs, and related compounds are called eicosanoids, from the Greek eikosi ("twenty"). Precursor essential fatty acids contain 20 carbons and 3, 4, or 5 double bonds. Arachidonic acid (AA; 5,8,11,14-eicosatetraenoic acid) is the most abundant precursor, derived from dietary linoleic acid (9,12-octadecadienoic acid) or ingested directly as a dietary constituent.

BIOSYNTHESIS. Biosynthesis of eicosanoids is limited by the availability of AA and depends primarily on the removal of esterified AA from membrane phospholipids or other complex lipids by acyl hydrolases, notably phospholipase A2 (PLA2). Once liberated, AA is metabolized rapidly to oxygenated products by cyclooxygenases (COXs), lipoxygenases (LOXs), and CYPs (Figure 33–1).

Figure 33–1

Metabolism of arachidonic acid (AA). The cyclooxygenase (COX) pathway is highlighted in gray. The lipoxygenase (LOX) pathways are expanded in Figure 33–2. Major degradation pathways are shown in Figure 33–3. Cyclic endoperoxides (PGG2 and PGH2) arise from the sequential cyclooxygenase and hydroperoxidase actions of COX-1 or COX-2 on AA released from membrane phospholipids. Subsequent products are generated by tissue-specific synthases and transduce their effects via membrane-bound receptors (blue boxes). Dashed lines indicate putative ligand-receptor interactions. Epoxyeicosatrienoic acids (EETs; shaded in blue) and isoprostanes are generated via CYP activity and non-enzymatic free radical attack, respectively. COX-2 can use modified arachidonoylglycerol, an endocannabinoid, to generate the glyceryl prostaglandins. Aspirin and tNSAIDs are nonselective inhibitors of COX-1 and COX-2 but do not affect LOX activity. Epilipoxins are generated by COX-2 following its acetylation by aspirin (see Figure 33–2). Dual 5-LOX-COX inhibitors interfere with both pathways. See the text for other abbreviations.

Chemical and physical stimuli activate the Ca2+-dependent translocation of group IVA cytosolic PLA2 (cPLA2) to the membrane, where it hydrolyzes the sn-2 ester bond of membrane phosphatidylcholine and phosphatidylethanolamine, releasing AA. Multiple additional PLA2 isoforms (secretory [s] and Ca2+-independent [i] forms) have been characterized. Under basal conditions, ...

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