Some of the most potent effects of PUFA are related to their enzymatic conversion into a series of oxygenated metabolites called eicosanoids, so-named because their precursors are PUFA with chain lengths of 20 carbon units. Eicosanoids include PG, thromboxane (TXA), leukotrienes (LT), hydroxy fatty acids, and lipoxins. PG and TXA are generated via cyclooxygenase (CO) enzymes, whereas LT, hydroxy acids, and lipoxins are produced from lipoxygenase (LO) metabolism. Under stimulation, rapid and transient synthesis of active eicosanoids activates specific receptors locally in the tissues in which they are formed. Eicosanoids modulate cardiovascular, pulmonary, immune, reproductive, and secretory functions in many cells. They are rapidly converted to their inactive forms by selective catabolic enzymes.
Humans depend on the dietary presence of the n-3 and n-6 structural families of PUFA for adequate biosynthesis of eicosanoids. There are three direct precursor FA from which eicosanoids are formed by the action of membrane-bound CO or specific LO enzyme systems: C20:3n-6, C20:4n-6, and C20:5n-3. A series of prostanoids and LT with different biologic properties are generated from each of these FA ( Fig, 4,7). The first irreversible, committed step in the synthesis of PG and LT is a hydroperoxide-activated FA oxygenase action exerted by either prostaglandin H synthase (PGHS) or LO enzymes on the nonesterified precursor PUFA ( Fig, 4.3).
Figure 4.7. Formation of PG, TXA, and LT from DHGA (C20:3n-6), arachidonic acid (C20:4n-6), and EPA (C20:5n-3) via cyclooxygenase and lipoxygenase pathways. LT, leukotriene; PG, prostaglandin; TXA, thromboxane.
Figure 4.8. Major pathways of synthesis of eicosanoids from arachidonic acid. PG, prostaglandin; HPETE, hydroperoxyeicosatrienoic acid; HETE, hydroxy fatty acid; diHETE, dihydroxyeicosatetranoic acid. (From Innis SM. Essential dietary lipids. In: Ziegler EE, Filer LJ, eds. Present knowledge in nutrition. 7th ed. Washington, DC: ILSI Press, 1996;58-66, with permission.)
Stimulation of normal cells via specific physiologic or pathologic stimuli, such as thrombin, adenosine diphosphate (ADP), or collagen, initiates a calcium-mediated cascade. This cascade involves phospholipase A2 activation, which releases PUFA on position 2 of cell membrane. The greatest proportion of PUFA available to phospholipase A2 action contains C20:4n-6. Hydrolytic release from PL esters appears to occur indiscriminantly with n-3 and n-6 types of PUFA and to involve all major classes of PL, such as PC, phosphatidyl ethanolamine (PE), and phosphatidyl inositol (PI). These FA serve as direct precursors for generation of eicosanoid products via CO and LO enzymatic action (Fig 4.8). Enzymatic biotransformation of the PUFA precursors to PG is catalyzed via two PG synthase isozymes designated PGH synthase-1 (PGHS-1) and PGH synthase-2 (PGHS-2) (98). PGHS-1 is located in the ER and PGHS-2 is located in the nuclear envelope. Both forms are bifunctional enzymes that catalyze the oxygenation of C20:4n-6 to PGG 2 via CO reaction and the reduction of PGG2 to form a transient hydroxyendoperoxide (PGH2) via the peroxidase reaction (Hg.4.8). The PGH2 intermediate is rapidly converted to PGI2 by vascular endothelial cells, to TXA2 by an isomerase in platelets, or to other prostanoids, depending on the tissues involved. The PGHS-2 generates prostanoids associated with mitogenesis and inflammation and is inhibited by glucocorticoids. On the other hand, PGHS-1 is expressed only after cell activation and is inhibited by nonsteroidal antiinflammatory drugs such as aspirin but not by glucocorticoids.
C20:4n-6 can be oxygenated via the 5-, 12-, and 15-LO pathways (Fig.4.7). From C20:4n-6, the 5-LO pathway generates mainly LTB4, LTC4, and LTD4, which are implicated as important mediators in a variety of proliferative and synthetic immune responses. LTB 4 in particular has been indicated a key proinflammatory mediator in inflammatory and proliferative disorders (98). From C20:4n-6, the 12-LO pathway generates 12-L-hydroxyeicosatetranoic acid (12-HETE) and 12-hydroperoxyeicosatetranoic acid (12-HPETE). A proinflammatory response can be generated by 12-HeTe in a variety of cell types. Products generated from C20:4n-6 metabolism by the 15-LO reaction include 15-hydroxyeicosatetranoic acid (15-HETE), which has antiinflammatory action and may inhibit 5- and 12-LO activities (99).
Since the major eicosanoids are synthesized from C20:4n-6, the availability of C20:4n-6 in PL pools of tissue may be a primary factor in regulating the quantities of eicosanoids synthesized by tissues in vivo. Also, the intensity of the n-6 eicosanoid signal from the released PUFA will be greater as C20:4n-6 becomes a greater proportion of the PUFA. The levels of C20:4n-6 in tissue PL pools are affected by the elongation and desaturation of dietary C18:2n-6 and by intake of C20:4n-6 (170-220 mg/day in the Western diet) (100). Although dietary concentrations of C18:2n-6 up to 2 to 3% of calories increase tissue C20:4n-6 concentrations, intake of C18:2n-6 above 3% of calories is poorly correlated with tissue C20:4n-6 content (101). Since C18:2n-6 constitutes approximately 6 to 8% of the North American diet, moderate dietary changes in C18:2n-6 would not be expected to modulate tissue C20:4n-6 levels. Intakes of C18:2n-6 above 12%, however, may actually decrease tissue C20:4n-6 because of inhibition of D6 desaturase. In contrast, dietary C20:4n-6 is much more effective in enriching C20:4n-6 in tissue PL (101) and, compared with C18:2n-6, relatively low dietary levels of C20:4n-6 may be physiologically significant in enhancing eicosanoid metabolism ( 100).
Feeding diets high in n-3 FA results in substitution of C20:4n-6 by n-3 PUFA in membrane PL. This can suppress the response of C20:4n-6-derived eicosanoids by decreasing availability of the C20:4n-6 precursor and by competitive inhibition of C20:5n-3 for eicosanoid biosynthesis ( 102). Although less pronounced than the effect observed with C20:5n-3 and C22:6n-3 dietary supplementation, C18:3n-3-enriched diets suppress PGE 2 production by peripheral blood mononuclear cells in monkeys (102). C18:3n-3 could competitively inhibit desaturation and elongation of C18:2n-6 for conversion into C20:4n-6. The eicosanoids derived from n-3 are homologues of those derived from C20:4n-6 with which they compete (Fig 4,9), and they are associated with less active responses than n-6 eicosanoids when bound to the specific receptors.
Diets rich in competing and moderating FA (n-3 PUFA, C18:3n-6) may produce changes in the production of eicosanoids which are more favorable with respect to inflammatory reactions. For instance, the PGE3 formed from C20:5n-3 has less inflammatory effect than PGE2 derived from C20:4n-6. The LTB5 derived from C20:5n-3 is substantially less active in proinflammatory functions than the LTB 4 formed from C20:4n-6, including the aggregation and chemotaxis of neutrophils. Two 15-LO products, 15-HEPE and 17-hydroxydocosahexanoic acid (17-HoDHE), are derived from C20:5n-3 and C22:6n-3, respectively ( 99). Both metabolites are potent inhibitors of LTB4 formation.
Overproduction of C20:4n-6-derived eicosanoids has been implicated in many inflammatory and autoimmune disorders such as thrombosis, immune-inflammatory disease (e.g., arthritis, lupus nephritis), cancer, and psoriatic skin lesions, among others. Because the typical American appears to maintain n-6 PUFA in PL near the maximal capacity, some have suggested that the n-6-rich diet in the United States may contribute to the incidence and severity of eicosanoid-mediated diseases such as thrombosis and arthritis (103). Because platelet aggregation and activation are indicated to play a critical role in progression toward vascular occlusion and myocardial infarction, the counterbalancing roles of TXA 2 and PGI2 in cardiovascular functions have been emphasized. C20:4n-6 is required for platelet function as a precursor of the proaggregatory TXA2. Biosynthesis of TXA2 is the rate-limiting step in the aggregation of platelets, a key event in thrombosis. The effects of TXA 2 are counteracted by PGI2, a potent antiaggregatory agent that prevents adherence of platelets to blood vessel walls. Due to displacement of C20:4n-6 from membrane PL by C18:2n-6, C18:3n-6, and C20:3n-6, stepwise increases in dietary C18:2n-6 from 3 to 40% of calories actually decreased platelet aggregation, indicating inhibition of eicosanoid synthesis by these n-6 PUFA. However, the antithrombotic influence of C18:2n-6 is substantially less than that observed after high intake of n-3 PUFA-rich fish oils (104). This has been related to the observations that PGI3 generated from C20:5n-3 has antiaggregatory potency. Conversely, TXA3 derived from C20:5n-3 has a very weak proaggregatory effect while TXA2 synthesis is reduced (105). Chronic ingestion of aspirin (106) and n-3 PUFA reduces the intensity of TXA2 biosynthesis, which could decrease rates of cardiovascular mortality. However, epidemiologic studies on the effects of dietary n-3 FA on cardiovascular disease have been inconsistent. A recent prospective study demonstrated no protective effect of fish consumption on cardiovascular disease mortality and morbidity ( 107), whereas another showed protective effects in elderly persons who ate only small amounts of fish (108). Results of several studies suggest that C18:3n-6 and n-3 EFA are involved in the regulation of cell-mediated immunity and that administration of these FA may be beneficial in suppressing pathologic immune responses. For example, subjects with rheumatoid arthritis fed fish oils high in n-3 PUFA have consistently obtained symptomatic benefit in doubly blinded, randomized, controlled trials ( 109). Although it appears that inhibition of the proinflammatory eicosanoids LTB 4 and PGE2 can account for many of the protective effects of n-3 PUFA, decreased production of the cytokines interleukin-1b and tumor necrosis factor are also likely involved ( 110).
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