Arachidonic acid, leukotriene synthesis

Glucocorticosteroids are the most potent antiinflammatory agents available. They stabilize lysosomal membranes and reduce the concentration of proteolytic enzymes at the site of inflammation. They promote the synthesis of proteins called lipocortins which inhibit phospholipase-A2 and thus inhibit production of arachidonic acid, leukotrienes and prostaglandins. Furthermore, the expression of COX-II and through that the inflammatory effects of the licosanoids is inhibited. Glucocorticosteroids reduce the release of histamine from basophils, decrease capillary permeability and cause vasoconstriction. Glucocorticosteroids stimulate the loss of calcium with the urine and inhibit the resorption of calcium from the gut. 

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Calderwood, S.K., Bomstein, B., Famum, E.K.., Stevenson, M.A. (1989). Heat shock stimulates the release of arachidonic acid and the synthesis of prostaglandins and leukotriene B4 in mammalian cells. J. Cell. Physiol. 141, 325-333. 

Topical corticosteroids (Table 16-1) may halt synthesis and mitosis of DNA in epidermal cells and appear to inhibit phospholipase A, lowering the amounts of arachidonic acid, prostaglandins, and leukotrienes in the skin. These effects, coupled with local vasoconstriction, reduce erythema, pruritus, and scaling. As antipsoriatic agents, they are best used adjunc-tively with a product that specifically functions to normalize epidermal hyperproliferation. 

The other major arachidonic acid (AA) converting enzyme is an integral binding protein, 5-lipoxygenase, which is responsible for the initial transformation in a cascade of events towards the biosynthesis of leukotrienes. Leukotrienes are major mediators of numerous biological processes, including chemotaxis, and are implicated in hypersensitivity disorders like asthma. It was discovered in the early 1990s that another protein is necessary for the cellular synthesis of... 

Eicosanoid synthesis. Arachidonic acid is converted by cyclooxygenases into prostaglandins, and thromboxanes. Lipoxygenases convert arachidonic acid into HPETEs, which are then converted to lipoxins, leukotrienes, and 12-HETE (hydroxyeicosatetraenoic acid). Epoxygenases convert arachidonic acid into epoxides. 

Aggregated IgE and A (mucosal surface) lacks C probably Arachidonic acid can lead to synthesis of PC s, thromboxanes, and leukotrienes in the lung and aggregation of platelets and release of histamine from platelets ... 

Before taking leave of the eicosanoids, 1 need to point out that a second enzyme, 5-lipoxygenase, also metabolizes arachidonic acid. 5-Lipoxygenase initiates the synthesis of the leukotrienes from arachidonic acid. There is a whole family of leukotrienes and these molecules have a spectrum of biological properties. 1 will focus on one important leukotriene, LTB4. 

The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLTi receptors. Montelukast and zafirlukast are competitive antagonists of these receptors. In contrast, zileuton suppresses synthesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes. Zileuton also blocks the production of leukotriene B4, another arachidonic acid metabolite with proinfiammatory activity. The CysLTi-receptor antagonists alter neither the production nor the actions of leukotriene B4. 

Another important aspect of the inflammatory cascade is arachidonic acid metabolism, leading to the synthesis of the proinflammatory prostaglandins and leukotrienes. Through the formation of Upocortin, an inhibitor of phospholipase A2, glucocorticoids depress the release of arachidonic acid from phospholipids and hence the production of arachidonic acid metabolites. 

Metabolites of arachidonic acid, including prostaglandins (PG), thromboxanes, and leukotrienes, are considered strong candidates as mediators of the inflammatory process. Steroids may exert a primary effect at the inflammatory site by inducing the synthesis of a group of proteins called lipocortins. These proteins suppress the activation of phospholipase A2, thereby decreasing the release of arachidonic acid and the production of proinflammatory eicosanoids (Fig. 60.6). 

Synthesis of prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—a microsomal protein that has two catalytic activities fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of the synthase COX-1 and COX-2. Leukotrienes are produced by the 5-lipoxygenase pathway. 

Sulfasalazine. Salicylazosulfapyridine or Azulfadine [599-79-1] (2-hydroxy-5-[[4[(2-pyridylamino)sulfonyl]-phenyl]azo] benzoic acid) (15) is a light brownish yellow-to-bright yellow fine powder that is practically tasteless and odorless. It melts at ca 255°C with decomposition, is very slightly soluble in ethanol, is practically insoluble in water, diethyl ether, chloroform, and benzene, and is soluble in aqueous solutions of alkali hydroxides. Sulfasalazine may be made by the synthesis described in Reference 13. It is not used as an antidiarrheal as such, but is indicated for the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn s disease. Its action is purported to result from the breakdown in the colon to 5-aminosalicylic acid [89-57-6] (5-AS A) and sulfapyridine [144-83-2]. It may cause infertility in males, as well as producing idiosyncratic reactions in some patients these reactions have been attributed to the sulfa component of the compound. The mechanism of 5-ASA is attributed to inhibition of the arachidonic acid cascade preventing leukotriene B4 production and the ability to scavenge oxygen free radicals. The active component appears to be 5-aminosalicylic acid. 

In addition to serving as a precursor for the synthesis of prostaglandins, arachidonic acid is also a precursor for the synthesis of prostacyclin, thromboxanes, and leukotrienes. 

The roles of leukotrienes and cytochrome P450 products in the human kidney are currently speculative. Recently, the 5,6-epoxide has been shown to be a powerful vasodilator in animal experiments. Another recent discovery is that free radicals attack arachidonic acid-containing phospholipids to yield an 8-ep/-PGF2[J that has powerful thromboxane-like properties. Synthesis is not blocked by COX inhibitors but can be blocked by antioxidants. This vasoconstrictor, which is present in humans, is thought to be another important mediator causing renal failure in the hepatorenal syndrome. 

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