ARACHIDONIC ACID & OTHER POLYUNSATURATED PRECURSORS
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).must first be released or mobilized from the sn-2 position of membrane phospholipids by one or more lipases of the phospho-lipase A2 (PLA2) type (Figure 18–1) for eicosanoid synthesis to occur. At least three classes of phospholipases mediate arachido-nate release from membrane lipids: cytosolic (c) PLA2, secretory
PLA2, and calcium-independent (i) PLA 2. Chemical and physical stimuli activate the Ca 2+-dependent translocation of group IVA cPLA2, which has high affinity for AA, to the mem-brane, 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 iPLA 2 is reincorporated into cell membranes, so there is negligible eicosanoid biosynthesis. While cPLA2 dominates in the acute release of AA, inducible sPLA2 contributes under condi-tions of sustained or intense stimulation of AA production. AA can also be released by a combination of phospholipase C and diglyceride lipase.
Following mobilization, AA is oxygenated by four separate routes: the cyclooxygenase (COX), lipoxygenase, P450 epoxyge-nase, and isoeicosanoid pathways (Figure 18–1). Among factors determining the type of eicosanoid synthesized are (1) the sub-strate lipid species, (2) the type of cell, and (3) the manner in which the cell is stimulated. Distinct but related products can be
AA Arachidonic acid
DHET Dihydroxyeicosatrienoic acid
EET Epoxyeicosatrienoic acid
HETE Hydroxyeicosatetraenoic acid
HPETE Hydroxyperoxyeicosatetraenoic acid
LTB, LTC Leukotriene B, C, etc
LXA, LXB Lipoxin A, B
NSAID Nonsteroidal anti-inflammatory drug
PGE, PGF Prostaglandin E, F, etc
PLA, PLC Phospholipase A, C
TXA, TXB Thromboxane A, B
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 (TXA 2), a powerful vasoconstrictor and platelet agonist, is synthesized from AA via the COX pathway. COX metabolism of EPA yields TXA 3, which is relatively inactive. 3-Series prostaglandins, such as prostaglandin E3 (PGE3), can also act as partial agonists or antagonists thereby reducing the activity of their AA-derived 2-series counterparts. The hypothesis that dietary eicosapentaenoate substitution for arachidonate could reduce the incidence of cardiovascular disease and cancer is a focus of current investigation.