EAST AFRICA UNIVERSITY FACULTY : veterinary medicine BATCH : two SUBJECT : pathology ASSIGNMENT : arachidonic acid metabolism LACTURED :Dr. Mubarak (Barakat Al-Maliety) PREPARED :Abdisalam Mohamed Abdirisak Arachidonic acid metabolites Arachidonic acid is a fatty acid, which either comes directly from diet or from conversion of linoleic acid to arachidonic acid. Arachidonic acid is activated by C5a to form its metabolites through either cyda-oxygenase or lipo-oxygenase pathway. Cyda-oxygenase is fatty acid enzyme which act on arachidonic acid to form prostaglandin endoperoxidase (PGG) which is further transformed into prostaglandin like PGD2, PGE3, PGF2, which thromboxane A2 (Tx A2 ) and prostacydin (PG12). Prostaglandin acts on blood vessels to cause vasodilation , increased permeability bronchodilation except PGF2a, which is responsible for vasodilation and bronchocnstriction . thromboxane A2 is a vasoconstrictor, bronchoconstrictor ,and cause aggregation of platelets leading of increase function of imflammatory cells prostacylin is found to be responsible for vasodilation , bronchodilation and inhibitory action on platelet aggregation. Lipo-oxygnase acts on arachidonic acid to form hydroperoxy eicosatetraenoic acid (SHPETE) which is further converted into ( SHETE ) a chemotactic agent for neutrophils and leucotrienes (LT) or slow reacting substance of anaphylaxis (SRS-A) the leucotrienes include an unstable form leucotriene A(LTA), which is soon converted into leucotriene B(LTB) achemotactic and adherence factor for phagocytic cells and leucotrience C, D and E (LTC, LTD , LTE )causing contraction of smooth muscles leading to vasoconstriction , bronchoconstriction and increased vascular permeability Arachidonic acid cascade AA is a long chain polyunsaturated fatty acid containing 20 carbons. It can be stored in membrane phospholipids and released from nuclear envelop or plasma membrane by cytosolic phospholipase A2 (cPLA2), either constitutively or in respond to a variety of cell specific stimuli, including growth factors, hormones, cytokines, signaling molecules, trauma. Free AA can be subsequently metabolized by three key enzymes, COX, LOX, or cytochrome P450 (CYP450) to generate lipid mediators, eicosanoids, which involved in various biological function, inflammation regulation, and more recently, tumor progression ( Wang et al., 2007; Hyde & Missailidis, 2009). COX metabolism generates prostanoids, including prostaglandins (PGs) and thromboxanes (TXs). LOX generates leukotrienes (LTs), lipoxin (LXs) and hepoxillins( HOs. CYP450 ) metabolic pathway gives a family of lipoxygenase-like hydroeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acid (EETs) and ω-HETEs (Capdevila et al., 2000) 2.1 The COX pathway In the COX pathway, COX first oxidized AA to form prostaglandin G2 (PGG2), and is then metabolized into an intermediate prostaglandin H2 (PGH2) by peroxidase activity (Figure 1). PGH2 is an unstable endoperoxide, which is catalyzed to five primary prostanoids, including PGD2, PGE2, PGF2, PGI2 and thromboxane A2 by specific synthases. Three isoforms of COX have been identified, COX-1, COX-2 and COX-3 (Williams et al., 1999; Wang et al., 2007). COX-1 and COX-2 are similar in structure and catalytic activity. Both enzymes have the same molecular weight and share a 61% amino acid sequence homology. COX-3 is the splice variants of COX-1, which retains intron 1 and has a frameshift mutation (Wang et al., 2007). COX-3 was constitutively highest expressed in the cerebral cortex and heart tissue (Chandrasekharan et al., 2002). COX-1 is constitutively expressed in almost all tissues and resident inflammatory cells. It generates PGs that control homeostasis. COX-2 is normally undetectable. Constitutive COX-2 expression is well recognized in brain, kidney and the female reproductive tract. However, COX-2 is the most important regulator in the respond to inflammation and many types of cancers. COX-2 can be induced by multiple cytokines and growth factors, via activation of transcription factors that act on the promoter region, including TATA box, and NF-IL6 motif, two AP-2 sites, three Sp1 sites, two NF-κB sites, a CRE motif and an E-box (Park et al., 2006). The PGEs subclass, including cytosolic PGE synthase (cPGEs) and membrane-bound PGE synthases (mPGEs), is also involved in inflammation and carcinogenesis. Once the various PGs are synthesized, they are exported into the extracellular microenvironment and bind to the specific G-protein coupled receptors (GPCRs) that can be activated by autocrine and paracrine fashions in the tumor microenvironment (Sugimoto & Narumiya, 2007). Fig. 1. Main products and enzymes of the COX pathway. COX: cyclooxygenase; PG: prostaglandin; TX: thromboxane
Posted on: Mon, 26 Jan 2015 14:16:46 +0000
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