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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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Acronyms
AAArachidonic acid
COXCyclooxygenase
DHETDihydroxyeicosatrienoic acid
EETEpoxyeicosatrienoic acid
HETEHydroxyeicosatetraenoic acid
HPETEHydroxyperoxyeicosatetraenoic acid
LTB, LTCLeukotriene B, C, etc
LOXLipoxygenase
LXA, LXBLipoxin A, B
NSAIDNonsteroidal anti-inflammatory drug
PGE, PGFProstaglandin E, F, etc
PLA, PLCPhospholipase A, C
TXA, TXBThromboxane A, B
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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). 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. At least three classes of phospholipases mediate arachidonate release from membrane lipids: cytosolic (c) PLA2, secretory (s) PLA2, and calcium-independent (i) PLA2. Chemical and physical stimuli activate the Ca2+-dependent translocation of group IVA cPLA2, which has high affinity for AA, to the membrane, where it releases arachidonate. Multiple additional PLA2 isoforms (group VI iPLA2 and sPLA2 from groups IIA, V, and X) have been characterized. 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 by a combination of phospholipase C and diglyceride lipase.

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Figure 18–1
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Pathways of arachidonic acid (AA) release and metabolism.

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Following mobilization, AA is oxygenated by four separate routes: the cyclooxygenase (COX), lipoxygenase, P450 epoxygenase, and isoeicosanoid pathways (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) or eicosapentaenoic acid (C20:5–3, EPA) yields products that differ quantitatively and qualitatively from those derived from AA. This shift in product formation is the basis for using fatty acids obtained from cold-water fish or from plants as nutritional supplements in humans. For example, thromboxane (TXA2), a powerful vasoconstrictor ...

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