Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

Snider, Natasha T.; Walker, Vyvyca J.; Hollenberg, Paul F.

doi:10.1124/pr.109.001081

Cited by 116 publications

(79 citation statements)

References 182 publications

(198 reference statements)

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“…5,6-epoxyeicosatrienoic acid ethanolamide (5,6-EET-EA) generated by P450-mediated catabolism of AEA is a potent agonist at CB2 receptors [29]. Interestingly, 5,6-EET-EA is also reported to be far more stable than AEA, while having little affinity at CB1 receptors [29], although it does act as a ligand at TRPV4 (see Snider et al [117]). Although the impact of chronic pain states on the expression of P450s (e.g.…”

Section: Effects Of Novel Biological Metabolites Of 2-ag and Anandamidementioning

confidence: 99%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

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Section: Effects Of Novel Biological Metabolites Of 2-ag and Anandamidementioning

confidence: 99%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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“…5A). The EET-EAs can be further metabolized by epoxide hydrolase to their corresponding dihydroxyeicosatrienoic acid ethanolamides (DHET-EAs) (Snider et al, 2007(Snider et al, , 2010. To determine the relative contribution of brain epoxide hydrolase activity to the disappearance of 14,15-EET-EA, we measured the amount of 14,15-DHET-EA formed in the presence and absence of PMSF.…”

Section: Sridar Et Almentioning

confidence: 99%

“…In addition to hydrolysis by FAAH, anandamide is oxygenated by several human cytochrome P450 enzymes, including 3A4, 4F2, 4X1, and the highly polymorphic 2D6, forming a number of metabolites that are likely to have important physiological roles (Snider et al, 2010). For example, the epoxide of anandamide at position C5-C6 formed by hepatic CYP3A4 is a potent agonist at the CB2 receptor (Snider et al, 2009(Snider et al, , 2010.…”

Section: Introductionmentioning

confidence: 99%

“…For example, the epoxide of anandamide at position C5-C6 formed by hepatic CYP3A4 is a potent agonist at the CB2 receptor (Snider et al, 2009(Snider et al, , 2010. Human CYP2D6.1 metabolizes anandamide to produce five monooxygenated metabolites, including a hydroxylated product, the 20-hydroxyeicosatetraenoic acid ethanolamide (HETE-EA), and four epoxides, the 5, 6-, 8,9-, 11,12-, and 14,15-epoxyeicosatetraenoic acid ethanolamides (Snider et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

2011

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ABSTRACT:Anandamide is an arachidonic acid-derived endogenous cannabinoid that regulates normal physiological functions and pathophysiological responses within the central nervous system and in the periphery. Several cytochrome P450 (P450) isoforms metabolize anandamide to form hydroxylated and epoxygenated products. Human CYP2B6 and CYP2D6, which are expressed heterogeneously throughout the brain, exhibit clinically significant polymorphisms and are regulated by external factors, such as alcohol and smoking. Oxidative metabolism of anandamide by these two P450s may have important functional consequences for endocannabinoid system signaling. In this study, we investigated the metabolism of anandamide by wild-type CYP2B6 (2B6.1) and CYP2D6 (2D6.1) and by their common polymorphic mutants 2B6.4, 2B6.6, 2B6.9, and 2D6.34. Major differences in anandamide metabolism by the two isoforms and their mutants were found in vitro with respect to the formation of 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 14,15-epoxyeicosatetraenoic acid ethanolamide (14,15-EET-EA). Pharmacological studies showed that both 20-HETE-EA and 14,15-EET-EA bind to the rat brain cannabinoid CB1 receptor with lower affinities relative to that of anandamide. In addition, both products are degraded more rapidly than anandamide in rat brain homogenates. Their degradation occurs via different mechanisms involving either fatty acid amide hydrolase (FAAH), the major anandamide-degrading enzyme, or epoxide hydrolase (EH). Thus, the current findings provide potential new insights into the actions of inhibitors FAAH and EH, which are being developed as novel therapeutic agents, as well as a better understanding of the interactions between the cytochrome P450 monooxygenases and the endocannabinoid system.

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“…Ca 2+ , ERK, Akt) and G proteins can be activated (Walker et al, 2010). There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ENSG00000126522) is important for the coupling of CLR to adenylyl cyclase (Evans et al, 2000).…”

Section: Calcitonin Amylin Cgrp and Adrenomedullinmentioning

confidence: 99%

Ligand-gated Ion Channels

Encyclopedic Reference of Molecular Pharmacology

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Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

Cited by 116 publications

References 182 publications

Dynamic changes to the endocannabinoid system in models of chronic pain

Dynamic changes to the endocannabinoid system in models of chronic pain

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

Ligand-gated Ion Channels

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