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INTRODUCTION

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The eicosanoids are oxygenation products of polyunsaturated long-chain fatty acids. They are ubiquitous in the animal kingdom and are also found—together with their precursors—in a variety of plants. They constitute a very large family of compounds that are highly potent and display an extraordinarily wide spectrum of biologic activity. Because of their biologic activity, the eicosanoids, their specific receptor antagonists and enzyme inhibitors, and their plant and fish oil precursors have great therapeutic potential.

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ARACHIDONIC ACID & OTHER POLYUNSATURATED PRECURSORS

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Arachidonic acid (AA), or 5,8,11,14-eicosatetraenoic acid, the most abundant of the eicosanoid precursors, is a 20-carbon (C20) fatty acid containing four double bonds (designated C20:4–6). The first double bond in AA occurs at 6 carbons from the methyl end, defining AA as an omega-6 fatty acid. AA must first be released or mobilized from the sn-2 position of membrane phospholipids by one or more lipases of the phospholipase A2 (PLA2) type (Figure 18–1) for eicosanoid synthesis to occur. The phospholipase A2 superfamily consists of 15 groups, with at least three classes of phospholipases contributing to arachidonate release from membrane lipids: (1) cytosolic (c) PLA2, and (2) secretory (s) PLA2, which are calcium-dependent; and (3) calcium-independent (i) PLA2. Chemical and physical stimuli activate the Ca2+-dependent translocation of cPLA2, which has high affinity for AA, to the membrane, where it releases arachidonate. Arachidonate release via iPLA2 and various sPLA2 subtypes also has been examined. Under nonstimulated conditions, AA liberated by iPLA2 is reincorporated into cell membranes, so there is negligible eicosanoid biosynthesis. While cPLA2 dominates in the acute release of AA, inducible sPLA2 contributes under conditions of sustained or intense stimulation of AA production. AA can also be released from phospholipase C-generated diacylglcerol esters by the action of diacylglycerol and monoacylglycerol lipases.

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FIGURE 18–1

Pathways of arachidonic acid (AA) release and metabolism.

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Following mobilization, AA is oxygenated by four separate routes: enzymatically via the cyclooxygenase (COX), lipoxygenase, and P450 epoxygenase pathways; and nonenzymatically via the isoeicosanoid pathway (Figure 18–1). Among factors determining the type of eicosanoid synthesized are (1) the substrate lipid species, (2) the type of cell, and (3) the manner in which the cell is stimulated. Distinct but related products can be formed from precursors other than AA. For example, homo-γ-linoleic acid (C20:3–6), also an omega-6 fatty acid, or eicosapentaenoic acid (C20:5–3), an omega-3 fatty acid, yield products that differ quantitatively and qualitatively from those derived from AA. This shift in product formation is the basis for dietary manipulation of eicosanoid generation using fatty acids obtained from cold-water fish or from plants as nutritional supplements in humans. For example, thromboxane (TXA2), a powerful vasoconstrictor and platelet agonist, is synthesized from AA via the ...

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