Arachidonic acid cascade

Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

CYP5 synthesizes thromboxane A2, a fatty acid in the arachidonic acid cascade that causes platelet aggregation. Aspirin prevents platelet aggregation because it blocks the cyclooxygenases COX1 and COX2 which catalyze the initial step of the biotransformation of arachidonic acid to thromboxane and prostaglandins. 

CYP8A1 is the complementary enzyme to CYP5 in that it synthesizes prostacyclin in the arachidonic acid cascade. CYP8B1 catalyzes the steroid 12-alpha hydroxylation in the cholic acid biosynthesis. 

Dumuis, A, Sebben, M, Haynes, L, Pin, JP and Bockaert, J (1988) NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 336 68-70. 

A series of 4-arylpyrimidines that arc amine substituted at pyrimidine C-2 was prepared. FK360 was most effective from this group on both arachidonate-induced cerebral oedema in rats and as an in vitro inhibitor of lipid peroxidation. The authors link effects of FK360 to the arachidonic acid cascade (Kuno et al., 1992). This is an unusual structure. 

There is some evidence that in cells with low anandamide amidase activity, such as platelets and neutrophils, anandamide is inactivated by an oxidative pathway involving 12(5)-lipoxygenase (Edgemond, 1998). Metabolism of anandamide by enzymes of the arachidonic acid cascade... 

Anggadiredja, K., Nakamichi, M., Hiranita, T. et al. Endocannabinoid system modulates relapse to methamphetamine seeking possible mediation by the arachidonic acid cascade. Neuropsychopharmacology. 29 1470, 2004. 

Activation of the arachidonic acid cascade during ischemia-reperfusion is a multistage process 586... 

The nonopioids are preferred over the opioids for mild to moderate pain (see Table 54-1). The salicylates and nonsteroidal antiinflammatory drugs (NSAIDs) reduce prostaglandins produced by the arachidonic acid cascade, thereby decreasing the number of pain impulses received by the CNS. 

An immediate reaction occurs within seconds to minutes, resulting in the rapid release of preformed mediators and newly generated mediators from the arachidonic acid cascade. Mediators of immediate hypersensitivity include histamine, leukotrienes, prostaglandin, tryptase, and kinins. These mediators cause vasodilation, increased vascular permeability, and production of nasal secretions. Histamine produces rhinorrhea, itching, sneezing, and nasal obstruction. 

Fig. 10. Photoaffinity probes for studying G-protein interactions PLC/IP3/Ca2+ signaling pathways, and the arachidonic acid cascade ...

Cytochrome P450 pathways in human brain arachidonic acid cascade... 

Osawa. Chemistry of ginger components and inhibitory factors of the arachidonic acid cascade. Asc Symp Z0145 Ser 1994 547 244-250. 

The arachidonic acid cascade is a biological free radical oxidation of unsaturated fatty acids leading to formation of the prostaglandins (equation 102). Cyclization of a peroxy radical intermediate 66 leading to endoperoxide 67 was proposed as a pathway for this process, and this was demonstrated in chemical model systems, in which the peroxyl radical 66 was generated by hydrogen abstraction from the hydroperoxide corresponding to 66. 

The basis for the analgesic action of NSAIDs is their ability to prevent the production of prostaglandins. Prostaglandins are derived from the arachidonic acid cascade and are implicated in the production of inflammatory pain and in sensitizing nociceptors to the actions of other mediators. 

Metabolites in Model Systems Related to Arachidonic Acid Cascade, Arzneim.-Forsch./Drug Res. 1983, 35, 947-952. 

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