Prostaglandins and other eicosanoids are produced by the oxidative metabolism of free arachidonic acid. Under normal circumstances, arachidonic acid is not available for metabolism as it is present as a conjugated component of the phospholipid matrix of most cellular membranes. Release of free arachidonic acid, which subsequently may be oxidatively metabolized, occurs by stimulation of phospholipase (PLA2) enzyme activity in response to some traumatic event (e.g., tissue damage, toxin exposure, or hormonal stimulation). It is believed that the clinical anti-inflammatory effect of glucocortical steroids (i.e., hydrocortisone) is a result of their ability to suppress PLA2 activity via lipocortins and thus prevent the release of free arachidonic acid.5 Modulation of PLA2 activity by alkali metal ions, toxins, and various therapeutic agents has become a major focus of biologic research because of the changes in eicosanoid production and the dramatic biological effects accompanying PLA2 stimulation or suppression. Although it was initially believed that the inflammatory response (swelling, redness, pain) was principally a result of PGE2, recent interest has focused on the interrelationships of PGE-type eicosanoids with the cy-tokines, such as interleukins-1 and -2, in the modulation of inflammatory reactions.6
Two different routes for oxygenation of arachidonic acid have been identified: the cyclooxygenase pathway (Fig. 26.1) and the lipoxygenase pathway (Fig. 26.2). The relative significance of each of these pathways may vary in a particular tissue or disease state. The cyclooxygenase pathway, so named because of the unusual bicyclic endoperoxide (PGG2) produced in the first step of the sequence, involves the highly stereospecific addition of two molecules of oxygen to the arachidonic acid substrate, followed by subsequent enzyme-controlled rearrangements to produce an array of oxygenated eicosanoids with diverse biologic activities (see Table 26.2). The first enzyme in this pathway, PGH-synthase, is a hemoprotein that catalyzes both the addition of oxygen (to form PGG2) and the subsequent reduction (peroxidase activity) of the 15-position hydroperoxide to the 15-(S)-configuration alcohol (PGH2).7 PGH-synthase (also called cyclooxygenase-1[COX-1] or -2 [COX-2], and formerly PG-synthetase) has been the focus of intense investigation because of its key role as the first enzyme in the arachidonic acid cascade.8 It is this enzyme in constitutive (COX-1) or inducible form (COX-2) that is susceptible to inhibition by NSAIDs, leading to relief of pain, fever, and inflammation.6,9 This enzyme is also inhibited by the m-3 (omega-3) fatty acids (EPA and docosahexaenoic acid [DHA]) found in certain cold-water fish, which are provided commercially as nutritional supplements, leading to beneficial cardiovascular effects.10 Cyclooxygenase will
metabolize 20-carbon fatty acids with one more or one less double bond than arachidonic acid, leading to prostaglandins of varied degrees of unsaturation (e.g., PGE1 or PGE3, for which the subscript number indicates the number of double bonds in the molecule).
Prostaglandin H2 serves as a branch-point substrate for specific enzymes, leading to the production of the various prostaglandins, TXA2, and PGI2. Even though most tissues can produce PGH2, the relative production of each of these derived eicosanoids is highly tissue specific and may be subject to secondary modulation by various cofactors. The complete characterization of enzymes involved in branches of the cyclooxygenase pathway and their genetic origins is currently under way.11
Specific cellular or tissue responses to the eicosanoids are apparently a function of available surface receptor recognition sites.12 The various tissue responses observed on eicosanoid exposure is outlined in Table 26.2. Nontissue-selective inhibitors of the cyclooxygenase pathway, such as aspirin, thus may exert a diversity of therapeutic effects or side effects (e.g., decreased uterine muscle contraction and platelet aggregation, gastric ulceration, lowering of elevated body temperature, central and peripheral pain relief, and decreased vascular perfusion) based on the inhibitor's tissue distribution profile.
The lipoxygenase pathway of arachidonic acid metabolism (Fig. 26.2) produces various acyclic lipid peroxides
(hydroperoxyeicosatetraenoic acids [HPETEs]) and derived alcohols (hydroxyeicosatetraenoic acids [HETEs]).13 Although the specific biologic function of each of these lipoxygenase-derived products is not completely known, they are believed to play a major role as chemotactic factors that promote cellular mobilization toward sites of tissue injury. In addition, the glutathione (GSH) conjugates LKT-C4 and LKT-D4 are potent, long-acting bronchoconstrictors that are released in the lungs during severe hypersensitivity episodes (leading to their initial designation as the "slow-reacting substances of anaphylaxis" [SRSAs]). Because of the presumed benefit of preventing formation of LKTs in asthmatic patients, much research effort is being dedicated to the design and discovery of drugs that might selectively inhibit the lipoxygenase pathway of arachidonic acid metabolism, without affecting the cyclooxygenase pathway.14 Zileuton (Zyflo by Abbott Laboratories) specifically inhibits the 5-lipoxygenase (5-LO) pathway. It has been proposed that aspirin hypersensitivity in susceptible individuals may result from effectively "shutting down" the cyclooxygenase metabolic route, allowing only the biosynthesis of lipoxygenase pathway intermediates, including the bronchoconstrictive LKTs.14 Other drugs (i.e., Singulair) have been developed, which block the receptors for certain leukotrienes. Considerable effort has also been directed toward discovering inhibitors of 5-LO activating protein (FLAP), which affects this pathway.15
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