Eicosanoid metabolism

Arachidonic acid metabolism through eicosanoid biosynthesis is accompanied by the generation and subsequent utilization of oxygen-derived free radicals. Arachidonic acid, released from lipids as a result 

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Peroxidases are found in milk and in leukocytes, platelets, and other tissues involved in eicosanoid metabolism (Chapter 23). The prosthetic group is protoheme. In the reaction catalyzed by peroxidase, hydrogen peroxide is reduced at the expense of several substances that will act as electron acceptors, such as ascorbate, quinones, and cytochrome c. The reaction catalyzed by peroxidase is complex, but the overall reaction is as follows ... 

Knowles, S.O. and Donaldson, W.E., Lead disrupts eicosanoid metabolism, macrophage function, and disease resistance in birds, Biol. Trace Element Res. 60, 13, 1997. 

Stratmann K, Boland W, Muller DG (1992) Pheromones of marine brown algae a new branch of eicosanoid metabolism. Angew Chem Int Ed 3 1246-1248 Suzuki M, Matsuo Y, Takahashi Y, Masuda M (1995) Callicladol, a novel cytotoxic bromotriter-pene polyether from a Vietnamese species of the red algal genus Laurencia. Chem Lett 11 1045-1046... 

The eicosanoids are a group of signaling substances that arise from the C-20 fatty acid arachidonic add and therefore usually contain 20 C atoms (Greek eicosa = 20). As mediators, they influence a large number of physiological processes (see below). Eicosanoid metabolism is therefore an important drug target. As short-lived substances, eicosanoids only act in the vicinity of their site of synthesis (paracrine effect see p.372). 

Weissmann, G., Aspirin. Sci. Am. 264 84-90, 1991. An interesting article that discusses the mechanism of action of aspirin in connection with eicosanoid metabolism. 

The effects of onion and garlic on eicosanoid metabolism have mainly been studied by observing the effects of garlic and onion preparations on platelet aggregation and subsequent eicosanoid synthesis. 

Ali, M., Thomson, M., and Afzal, M., Garlic and onions their effect on eicosanoid metabolism and its clinical relevance, Prostaglandins Leukot. Essent. Fatty Acids, 62, 55-73, 2000. 

Fischer, M.A. and Black, H.S., Modification of membrane composition, eicosanoid metabolism, and immunoresponsiveness by dietary omega-3 and omega-6 fatty acid sources, modulators of ultraviolet-carcinogenesis, Photochem. Photobiol., 54, 381, 1991. 

Prenylated flavonoids contain one or two isoprenyl, geranyl, dimethylallyl, and lavandulyl on the skeleton. They have limited distribution and are mostly isolated from the Moraceae family. Chi et al. isolated 19 prenylated flavonoids from six different genera of Chinese medicinal plants and evaluated inhibition activities on eicosanoid metabolisms with multiple cell line models [189]. Two 8-lavandulylated flavanones, kurarinone and sophoraflavanone G, were discovered to be dual inhibitors. They possessed the most potent COX-1 inhibitory activities with IC50 less than 1 pM comparable with that of indomethacin. Sophoraflavanone G isolated from the roots of Sophora flavescense Art (Fabaceae) also had potent 5-LOX inhibition activity with an IC50 below 0.25 pM. 

Figure 12.1. Overview of eicosanoid metabolism, a Stmetures of eicosanoid precursor fatty acids, and their occurrence in membrane phospholipids (PC is shown as an example). Araehidonie acid is the prototypic precursor eicosatrienoic and eicosapen-tanoic acid differ from it by the a lackingor an additional double bond, respectively, b Conversion of preemsor fatty acids occurs by various enzymes, notably cyclooxygenases and lipoxygenases. Isoprostanes are non-enzymahe derivatives that may form in vivo at appreciable rates one characterishc featme is that they occur as racemic mixtures. Their physiological significance is not entirely clear.

As you can see, the individual eicosanoid mediators t5 ical-ly have multiple roles from this, we can already infer that dmgs acting on the eicosanoid metabolism will be prone to side effects. 

Aside from sophisticated drug design, there is a surprisingly simple means of favourably influencing the balance of Good and Evil in eicosanoid metabolism Eating fish. As initially mentioned, aside from arachidonic acid, other multiply non-saturated fatty acids can serve as precursors of eicosanoid mediators as well, in particular eicosapentanoic acid (EPA), which has an additional double bond between C17 and Cl8. The introduction of this omega-3 double bond does not occur, nor is it reversible, in mammalian... 

Trans-Isomers and Cancer A study conducted in postmenopausal women suggested an association between risk of breast cancer and the level of hydrogenated oil derived mono-frawi-fatty acids was stored in the adipose tissue (221). It was also found that frawi-fatty acid might cause colorectal neoplasia by interfering with the cell membrane function or eicosanoid metabolism (222). Increased adenoma prevalence was associated with the consumption of sweetened baked goods, oils, and condiments. 

Experiments by Curtis et al. (129) gave evidence that the observed effects of n-3 fatty acids were not always mediated by the alterations in eicosanoid metabolism. In that study, supplementation of IE-1-stimulated cultured chondrocytes... 

The eicosanoid metabolic pathway as it is currently understood begins with the liberation of long-chain fatty acids from cell membranes. In mammalian tissues the primary fatty... 

Linoleic acid and LNA and their long-chain derivatives arc important components of animal and plant cell membranes. When humans ingest fish or fish oil, the EPA and DHA from the diet partially replace the omega-6 fatty acids, especially AA, in the membranes of probably all cells, but especially in the membranes of platelets, erythrocytes, neutrophils, monocytes, and liver cells [reviewed in Simopoulos, 19911. A diet that has a high ratio of omega-6 omega-3 fatty acids has detrimental effects on eicosanoid metabolism and gene expression. 

Wander RC, Hall JA, Gradin JL, Du SH, Jewell DE. The ratio of dietary (n-6) to (n-3) fatty acids influences immune system function, eicosanoid metabolism, hpid peroxidation and vitamin E status in aged dogs. J Nutr. 1997 127 1198-205. 

Perez-Novo CA, Claeys C, Van Zele T, Holtapples G, Van Cauwenberge P, Bachert C Eicosanoid metabolism and eosinophilic inflammation in nasal polyp patients with immune response to Staphylococcus aureus enterotoxins. Am J Rhinology 2006 20 456M60. 

EICOSANOID METABOLISM Regulation of Fatty Acid Metabolism in Mammals... 

Review the effects of aspirin and steroids on eicosanoid metabolism described in Special Interest Box 12.2. Suggest a reason why this information is relevant to the treatment of rheumatoid arthritis. Does, it explain the difference between the effectiveness of aspirin and steroids in treating inflammation ... 

The conversion of LTs into alternative structural entities is an important feature of inactivation of these potent biologically active eicosanoids. Metabolism of LTs is rapid and the exact pathway depends upon whether the substrate is LTB4 or LTC4. LTB4 is rapidly metabolized through both oxidative and reductive pathways (Fig. 9) [27]. The most prominent pathway present in human neutrophils (CYP4F3) as well as hepatocytes... 

Phospholipases are enzymes that can catalyze cleavage of acyl or phosphoacyl moieties from glycerophospholipids, as shown in Figure 19.6. Phospholipases are implicated in rearrangement of phospholipids after they have been synthesized and in release of arachidonic acid from glycerophospholipids in eicosanoid metabolism. 

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