Metabolism of Anandamide

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... 

See Vandevoorde, S. et al. Modifications of the Ethanolamine Head in N-Palmitoylethanolamine Synthesis and Evaluation of New Agents Interfering with the Metabolism of Anandamide. J Med Chem. (2003) 46(8) 1440-8 Lambert D.M, et al The Palmitoylethanolamide Family a New Class of Antiinflammatory Agents CurrMed Chem. (2002) (6) 663-74. 

Di Marzo V, De Petrocellis L, Bisogno T, Melck D (1999b) Metabolism of anandamide and 2-arachidonoylglycerol an historical overview and some recent developments. Lipids 34 319-325... 

Bisogno T, Ventriglia M, Milone A, Mosca M, Cimino G, Di Marzo V (1997) Occurrence and metabolism of anandamide and related acyl-ethanolamides in ovaries of the sea urchin Paracentrotus lividus. Biochim Biophys Acta 1345 338-348... 

Willoughby KA, Moore SF, Martin BR, EUis EF (1997) The biodisposition and metabolism of anandamide in mice. J Pharmacol Exp Ther 282 243-247... 

Burstein, S.H., Rossetti, R.G., Yagen, B., and Zurier, R.B. (2000) Oxidative metabolism of anandamide, Prostaglandins and Other Lipid Mediators 61 29-41. 

Matsuda, S., Kanemitsu, N., Nakamura, A., Mimura, Y., Ueda, N., Kurahashi, Y, and Yamamoto, S. (1997) Metabolism of anandamide, an endogenous cannabinoid receptor ligand, in porcine ocular tissues. Experimental Eye Research 64 707-711. 

There are currently five reported routes for the metabolism of anandamide, and these are outlined in Figure 8.9 (Di Marzo, De Petrocellis, et al., 1999). The principal route for the metabolism of anandamide is mediated by an amidase called FAAH that releases free arachidonic acid and ethanolamine (Ueda et al., 1997 Ueda, Katayama, et al., 1999 Ueda, Yamanaka, et al., 1999 Ueda et al., 2000 Ueda and Yamamoto, 2000 Ueda, 2002). The free acid could either be re-incorporated into phospholipids or transformed into eicosanoids with potent biological actions of their own. At this time there is little evidence to support the latter suggestion however, should this turn out to be true, it would have interesting implications for the mechanism of anandamide action. This hydrolytic transformation of anandamide is considered to be an important physiological mechanism for regulating in vivo levels of anandamide, and FAAH has become a popular target for therapeutic intervention where it is desired to maintain or elevate anandamide tissue concentrations. 

FIGURE 8.9 Metabolism of anandamide. The bioconversions shown are either taken from published reports (established), or are proposed in this review (putative). ACGNAT acyl-CoA glycine iV-acyltransferase. 

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... 

FIGURE 12.2 Oxidative metabolism of anandamide by cyclooxygenase (COX) and lipoxygenase (LOX) to yield ethanolamide (EA) derivatives. 

Indeed, mass spectrometric analysis shows that capsaicin and depolarization (KCl) induce significant release of anandamide in DRG cultures (Ahluwalia et al., 2003). It is perhaps notable that the capsaicin-evoked release of anandamide is significantly attenuated when the FAAH inhibitor MAFP is excluded from the buffer, demonstrating that anandamide is rapidly metabolized in DRG neurons. Metabolic products of anandamide have also been implicated in anandamide-induced depolarization of the guinea-pig isolated vagus nerve, which is TRPV1-receptor mediated (Kagaya et al., 2002). In this preparation, depolarization by anandamide but not capsaicin is inhibited by LOX inhibitors, but only in the presence of calcium. It is not clear, however, whether these active metabolites are produced via direct LOX metabolism of anandamide or via metabolism of arachi-donic acid, because these experiments did not include FAAH inhibitors. 

Potent FAAH inhibitors have recently been synthesized that enhance the levels of anandamide significantly, and these compounds may have considerable therapeutic potential (Boger et al., 2000). In the event of inhibition of FAAH metabolism of anandamide, increased levels of endogenous anandamide may lead to the production of significant levels of the HPETE ethanolamides. In addition, LOX metabolism producing metabolites that are FAAH inhibitors (van der Stelt et al., 2002) of anandamide may enhance TRPV 1 receptor activation by increasing the levels of available anandamide. 

The metabolism of anandamide is a variable process that differs in various cell types. It is metabolized by COX and LOX to form families of novel lipids that are pharmacologically active. Some enzymes display low activity toward anandamide nevertheless, in the absence of other metabolic alternatives, such pathways may become significant. The physiological importance of these novel metaboUc pathways remains to be established. 

Anandamide produces a number of in vivo pharmacological effects in CBj knockout mice that are not produced by A -THC and caimot be explained by the rapid metabolism of anandamide. To date, pharmacological data suggest the possibility of additional camiabinoid receptors, both in the brain and the periphery (Wiley and Martin, 2002). Thus, investigations in this field should be continued. 

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