Arachidonic acid oxygenated products

Davies, R, Bailey, PJ., Goldenbetg, MM., and Ford-Hutchin-son, A.W. (1984) The Role of Arachidonic Acid Oxygenation Products in Pain and Inflammation, Anna. Rev. Immunol. 2, 335-357. 

Any of the collection of oxygenated metabolites of arachidonic acid that are the product of cyclooxygenase, cytochrome P450, or lipoxygenase pathways. 

Free radicals are by-products of prostaglandin metabolism and may even regulate the activity of the arachidonate pathway. Arachidonic acid, released from lipids as a result of activation of phospholipases by tissue injury or by hormones, may be metabolized by the prostaglandin or leu-kotriene pathways. The peroxidase-catalysed conversion of prostaglandin G2 to prostaglandin H2 (unstable prostanoids) and the mechanism of hydroperoxy fatty acid to the hydroxy fatty acid conversion both yield oxygen radicals, which can be detected by e.s.r. (Rice-Evans et al., 1991). 

Nitric oxide and peroxynitrite contribute to oxidative damage 569 Production of eicosanoids from polyunsaturated fatty acids such as arachidonic acid may generate reactive oxygen species 570 Brain antioxidant defenses modify ischemia-reperfusion injury 570 Reactive oxygen species may modify both the excitotoxic and the apoptotic components of ischemic brain damage 570... 

Figure 6.17. Leukotriene formation in neutrophils. Arachidonic acid, which is released from membrane phospholipids by the action of either phospholipase A2 or diacylglycerol lipase (see Fig. 6.13), is oxygenated by 5-lipoxygenase to yield 5 hydroperoxy-6,8,11,14 eicosa-tetraenoic acid (5-HPETE). This is then converted into 5 hydroxy-6,8,11,14 eicosatetra-enoic acid (5-HETE) and leukotriene (LT) A4. LTA4 may then be enzymically converted into LTC4 and LTB4. LTB4 is the major product in activated neutrophils.

Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are complement components, cytokines, and other products of leukocytes and platelets. Stimulation of the neutrophil membranes produces oxygen-derived free radicals. Superoxide anion is formed by the reduction of molecular oxygen, which may stimulate the production of other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process. 

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. 

The importance of Tyr-385 in aspirin acetylation of Ser-530 suggests that it may play a broader role in interacting with electron-rich centers. In fact, the crystal structure of a catalytically inactive mutant of COX-2 with bound arachidonic acid reveals the arachidonate bound in an inverted, noncanonical orientation in which its carboxylate group is hydrogen-bonded to both Tyr-385 and Ser-530 (38). This conformation is not a productive conformation for arachidonate oxygenation, but... 

---