Anandamide oxygenation

Edgemond WS, Hlillard CJ, Falck JR, Kearn CS, Cambell WB. Fluman platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide) their affinities for canna-binoid receptors and pathways of inactivation. Mol Pharmacol 1998 54 180-188. 

Anandamide can be transported inside neural cells (neurons and glia) by a carrier-mediated facilitate diffusion mechanism (Beltramo et al., 1997) and transformed through two main pathways (1) hydrolysis to arachidonic acid and ethanolamine, and (2) oxidation to various oxygenated derivatives. 

Kozak KR, Piusakiewicz JJ, Rowhnson SW, Pmdhomme DR, Marnett LJ (2003) Amino acid determinants in cyclooxygenase-2 oxygenation of the endocannabinoid anandamide. Biochemistry 42 9041-9049 Kurahashi Y, Ueda N, Suzuki H, Suzuki M, Yamamoto S (1997) Reversible hydrolysis and synthesis of anan-... 

Thomas et al. were first to report a CoMFA QSAR pharmacophore model for anandamide (4) audits analogs (Thomas etal. 1996). These authors used molecular dynamics studies to explore conformations of 4 that present pharmacophoric similaritieswith2l -THC(l). A J-shaped or looped conformation of 4 was identified that had good molecular volume overlap with 1 when (1) the carboxyamide of 4 was overlaid with the pyran oxygen (0-5) in 1 (2) the head group hydroxyl of 4 was overlaid with the C-1 phenolic hydroxyl group of 1, (3) the five terminal carbons of the 4 fatty acid acyl chain were overlaid with the C-3 pentyl side chain of 1 and... 

Yu et al. (1997) demonstrated that anandamide is oxygenated by COX-2, whereas COX-1 does not display any detectable activity with anandamide as substrate. The major product of COX-2 metabolism of anandamide is PGEj ethanolamide. Furthermore, anandamide is oxygenated by COX-2 in the physiological environment in HFF cells that express both COX isoforms, prostaglandin ethanolamides are products of anandamide metabohsm in THP cells that express COX-1 only, there is no detectable metabolism. In RAW 264.7 macrophages, PGEj ethanolamide is synthesized from anandamide, and pretreatment of the cells with hpopolysaccharide (EPS), which is an inducer... 

Kinetic analysis reveals that 2-AG is oxygenated by both human and mouse COX-2, with K values similar to those obtained with arachidonic acid (Kozak et al., 2000). For hnman COX-2 the K valne is 60-fold higher than that reported for anandamide (Yu et al.,1997). In vitro, the main glycerol... 

Van der Stelt, M., Van Kuik, J.A., Bari, M., Van Zadelhoff, G., Eeeflang, B.R., Veldink, G.A., Einazzi-Agro, A., Vliegenthart, J.F.G., and Maccarrone, M. (2002). Oxygenated metabolites of anandamide and 2-arachidonoylglycerol conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase. J. Med. Chem., 45, 3709-3720. 

Anandamide may escape metabohc degradation by FAAH through its enzymatic oxygenation. It was shown that anandamide may be metabohzed by lipoxygenases (Ueda et al., 1995 Hampson et al., 1995 Edgemond et al., 1998), COX-2 (Yu et al., 1997), or P450 hydroxylates (Bomheim et al., 1993,1995). The functional significance of such metabolic conversion is yet to be identified. 

Ueda N, Yamamoto K, Kurahashi Y, Yamamoto S, Ogawa M, Matsuki N, Kudo I, Shinkai H, Shirakawa E, Tokunaga T. (1995) Oxygenation of arachidonylethanolamide (anandamide) by lipozygenases. Advances in Prostaglandin Thromboxane and Leukotriene Research 23 163-165. 

What is, then, the biogenesis of anandamide One of the aims of the present chapter is to review the last three years of research in this area and provide a possible answer to this question. I will also briefly describe what is currently known on other aspects of anandamide metabolism in brain tissue, in particular its hydrolytic degradation and oxygenation by lipoxygenase enzymes. Before we address these issues, however, it will be useful to review the biological effects of anandamide in the wider context of the multiple pharmacological properties of plant-derived and synthetic cannabinoid drugs. 

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