Emerging class of omega-3 fatty acid endocannabinoids & their derivatives - PubMed (original) (raw)

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Emerging class of omega-3 fatty acid endocannabinoids & their derivatives

Josephine E Watson et al. Prostaglandins Other Lipid Mediat. 2019 Aug.

Abstract

Cannabinoid receptor activation is involved in homeostatic regulation of the body. These receptors are activated by cannabinoids, that include the active constituents of Cannabis sativa, as well as endocannabinoids (eCBs). The eCBs are endogenously synthesized from the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). The consumption of omega-3 fatty acids shifts the balance towards a higher proportion of omega-3 eCBs, whose physiological functions warrants further investigation. Herein, we review the discovery of omega-3 fatty acid derived eCBs that are generated from long chain omega-3 PUFAs - docosahexaenoyl ethanolamide (DHA-EA or synaptamide), docosahexanoyl-glycerol (DHG), eicosapentaenoyl ethanolamide (EPA-EA) and eicosapentanoylglycerol (EPG). Furthermore, we outline the lesser known omega-3 eCB-like molecules that arise from the conjugation of omega-3 fatty acids with neurotransmitters serotonin and dopamine - DHA-serotonin (DHA-5HT), DHA-dopamine (DHA-DA), EPA-serotonin (EPA-5HT) and EPA-dopamine (EPA-DA). Additionally, we describe the role of omega-3 eCBs and their derivatives in different disease states, such as pain, inflammation and cancer. Moreover, we detail the formation and potential physiological roles of the oxidative metabolites that arise from the metabolism of omega-3 eCBs by eicosanoid synthesizing enzymes - cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 epoxygenase (CYP450). In summary, we outline the novel findings regarding a growing class of signaling molecules that can control the physiological and pathophysiological processes in the body.

Keywords: Cancer; Endocannabinoids; Inflammation; Metabolism; Omega-3 fatty acids.

Copyright © 2019 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflict of Interest Statement

The authors declare no competing financial interest.

Figures

Figure 1.

Figure 1.. Omega-3 endocannabinoids and derivatives.

Chemical Structures of (A) Omega-3 fatty acids, Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) and N-acyl amide derivatives that have been identified in literature. (B) Docosahexaenoyl ethanolamide (DHA-EA), Eicosapentaenoyl ethanolamide (EPA-EA), (C) 1-Docosahexaenoyl-glycerol (1-DHG), 1-Eicosapentaenoyl- glycerol (1-EPG), (D) DHA-Dopamine (DHA-DA), EPA-Dopamine (EPA-DA), DHA-Serotonin (DHA-5HT) and EPA-Serotonin (EPA-5HT).

Figure 2.

Figure 2.. Oxidation of Omega-3 endocannabinoids (DHA-EA and EPA-EA) by the LOX and CYP450 pathway.

(A) For the LOX pathway, oxidation can occur once and metabolites formed can undergo additionally oxidation or reduction to form seven DHA-EA-LOX metabolites; 17-hydroperoxydocosahexaenoyl ethanolamide (17-HpDHA-EA), 17-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoylethanolamide (17-HDHA-EA), 10,17-dihydroxydocosahexaenoyl ethanolamide (10,17-diHDHA-EA), 7,17-dihydroxydocosahexaenoyl ethanolamide (7,17-diHDHA-EA), 4,17-dihydroxydocosahexaenoyl ethanolamide (4,17-diHDHA-EA), 13-hydroxy-16(17)-epoxy-docosapentaenyolethanolamide (13-HEDPEA) and 15-hydroxy-16(17)-epoxy-docosapentaenyolethanolamide (15-HEDPEA). (B) The CYP450 pathway oxidizes DHA-EA and EPA-EA into six epoxydocosapentaenoic acid-ethanolamide (EDP-EA) and five epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) regioisomers, respectively.

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