Cyclooxygenases pathway

There are three groups of eicosanoids that are synthesized from C20 eicosanoic acids derived from the essential fatty acids linoleate and a-linolenate, or directly from dietary arachidonate and eicosapentaenoate (Figure 23-5). Arachidonate, usually derived from the 2 position of phospholipids in the plasma membrane by the action of phospholipase Aj (Figure 24-6)—but also from the diet—is the substrate for the synthesis of the PG2, 1X2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate (Figure 23-5). 

Figure 23-5. The three groups of eicosanoids and their biosynthetic origins. (PG, prostaglandin PGI, prostacyclin TX, thromboxane LT, leukotriene LX, lipoxin , cyclooxygenase pathway , lipoxygenase pathway.) The subscript denotes the total number of double bonds in the molecule and the series to which the compound...

Palytoxin is hemolytic (4) and is an extremely potent toxin (7). We have shown that in rat liver cells palytoxin stimulates de-esterification of cellular lipids to liberate arachidonic acid (5). These rat liver cells metabolize this increased arachidonic acid via the cyclooxygenase pathway to produce prostaglandin (PG) I2 and lesser amounts of PGE2 and PGp2. Palytoxin acts on many cells in culture to stimulate the production of cyclooxygenase metabolites (Table I). Clearly, the myriad pharmacological effects of the arachidonic acid metabolites must be considered in any explanation of the many clinical manifestations of palytoxin s toxicity. 

Prostaglandin Any of a large group of biologically active, carbon-20, unsaturated fatty acids that are produced by the metabolism of arachidonic acid through the cyclooxygenase pathway. 

A recent study showed THC to be toxic to hippocampal neurons, while sparing cortical neurons in concentrations likely to be reached in normal human doses (0.5 pM) (Chan et al. 1998). Apoptotic changes were noted in the hippocampus such as shrinkage of neuronal cell bodies and nuclei as well as DNA strand breaks. THC stimulates release of arachidonic acid, and it was hypothesized that this neurotoxic effect is mediated by cyclooxygenase pathways and free radical generation. In support of this, the toxicity is inhibited by nonsteroidal anti-inflammatory drugs, such as aspirin, and antioxidants such as vitamin E. 

Several ehemical enhancers, such as sodium ethylenediaminetetraacetate and sodium taurocholate, oleic acid [37], polyoxyethylated nonionic surfactants, citric acid, and dihydroxy bile salts open the paracellular route, presumably by disruption of the intraeellular OJC funetion [37], The use of nitrie oxide is another approach [39], Moreover, manipulation of the cyclooxygenase pathway activities to trigger the release of eompounds like substance P may provide another means for altering colonic permeability [40],... 

Figure 1.9. Overview of the biosynthesis of ecosanoids. The 20 carbon fatty acid arachidonic acid is released from cell membrane phospholipids by the actions of phospholipase A2. Free arachidonic acid forms the precursor of prostaglandins and thromboxanes via the multi-enz5une cyclooxygenase pathway, while leukotrienes are formed via the lipoxygenase pathway...

Prostaglandin (PC). Components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. 

NSAIDs exert analgesic, antipyretic, anti-inflammatory and related effects. During pain, fever and inflammation the arachi-donic acid is liberated from the phospholipid fraction of the cell membrane which is then converted to prostaglandins (PCs) via cyclooxygenase pathway (both COX-1 COX-2). COX-1 is present in kidney, stomach and blood vessels and COX-2 is present in activated leukocytes and other inflammatory cells. 

Cyclooxygenase pathway All eicosanoids with ring structures, that is, the prostaglandins, thromboxanes, and prostacyclins, are synthesized via the cyclooxygenase pathway. Two cyclooxygenases have been identified COX-1 and COX-2. The former is ubiquitous and constitutive, whereas the latter is induced in response to inflammatory stimuli. The products of these and subsequent reactions in this pathway are summarized in Figure 39.3. 

Pugsley TA, Spencer C, Boctor AM, Gluckman MI (1985) Selective inhibition of the cyclooxygenase pathway of the arachidonic acid cascade by the nonsteroidal antiinflammatory drug isoxicam. Drug Dev Res 5 171-178... 

The cyclooxygenase pathway may be interrupted at a number of stages.Two cyclooxygenase enzyme isoforms... 

Thromboxane A2 (TXi ), is a product of the cyclooxygenase pathway of arachidonic acid metabolism with platelet... 

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