Endocannabinoid metabolism by cytochrome P450 monooxygenases

The human body contains endogenous cannabinoids (endocannabinoids) that elicit similar effects as Δ9-tetrahydrocanabinol, the principal bioactive component of cannabis. The endocannabinoid virodhamine (O-AEA) is the constitutional isomer of the well-characterized cardioprotective and anti-inflammatory endocannabinoid anandamide (AEA). The chemical structures of O-AEA and AEA contain arachidonic acid (AA) and ethanolamine, however AA in O-AEA is connected to ethanolamine via an ester linkage whereas AA in AEA is connected through an amide linkage. We show that O-AEA is found at 9.6 fold higher levels than AEA in porcine left ventricle and is involved in regulating blood pressure and cardiovascular function. On a separate note, the cytochrome P450 (CYP) epoxygenase CYP2J2 is the most abundant CYP in the heart where it catalyzes the metabolism of AA and AA-derived eCBs to bioactive epoxides that are involved in diverse cardiovascular functions. Herein, using competitive binding studies, kinetic metabolism measurements, molecular dynamics and wound healing assays we have shown that O-AEA is an endogenous inhibitor of CYP2J2 epoxygenase. Together, the role of O-AEA as an endogenous eCB inhibitor of CYP2J2 may provide a new mode of regulation to control the activity of cardiovascular CYP2J2 in vivo and suggests a potential cross talk between the cardiovascular endocannabinoids and cytochrome P450 system.

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“…63,38 CPR was similarly expressed in E.coli and purified on a ADP agarose column. Nanodiscs were assembled based on previously reported methods.…”

Section: Resultsmentioning

confidence: 99%

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

et al. 2018

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“…They act as precursor pools for ARA for the subsequent production of eicosanoids [87] and are also converted to further classes of bioactive mediators. 2-AG and AEA are substrates for COX-2, producing prostamides and prostaglandin glycerol esters, LOX producing hydroperoxy derivatives (HPETE) and CYP enzymes, producing hydroxy-eicosatetraenoic ethanolamide molecules (HETE-EA) or epoxy-eicosatrienoic acids (EET) [30, 88, 89]. 2-AG can also be phosphorylated by acyl glycerol kinase(s) to produce lysophosphatidic acid (LPA) [66], another important bioactive lipid [90].…”

Section: Metabolism Of Pufa and Endocannabinoidsmentioning

confidence: 99%

“…(HPETE) and CYP enzymes, producing hydroxy-eicosatetraenoic ethanolamide molecules (HETE-EA) or epoxyeicosatrienoic acids (EET) [30,88,89]. 2-AG can also be phosphorylated by acyl glycerol kinase(s) to produce lysophosphatidic acid (LPA) [66], another important bioactive lipid [90].…”

Section: Metabolism Of Pufa and Endocannabinoidsmentioning

confidence: 99%

Interplay Between n‐3 and n‐6 Long‐Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair

Dyall

2017

Lipids

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The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.

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“…For example, CYPs convert AA and omega-3 PUFAs into epoxy-PUFAs that have been shown to decrease pain [53][54][55] . Recently, the CYP-mediated metabolism of eCBs was shown to produce epoxy-eCBs that exhibit CB2 receptor selectivity and are anti-inflammatory and anti-tumorigenic [56][57][58] . For instance, CYPs epoxidize AEA into epoxyeicosatrienoic acid ethanolamides (EET-EAs) that bind to CB2 receptors 56,59,60 .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the CYP-mediated metabolism of eCBs was shown to produce epoxy-eCBs that exhibit CB2 receptor selectivity and are anti-inflammatory and anti-tumorigenic [56][57][58] . For instance, CYPs epoxidize AEA into epoxyeicosatrienoic acid ethanolamides (EET-EAs) that bind to CB2 receptors 56,59,60 . Similarly, omega-3 PUFA-derived eCBs are also converted by CYPs into epoxide metabolites that are anti-inflammatory and antitumorigenic 57 .…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

Arnold

Carnevale

Xie³

et al. 2020

Preprint

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The endocannabinoid (eCB) system is a promising target to mitigate pain as the eCBs are endogenous ligands of the pain-mediating receptors-cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Here we report on a novel class of lipids formed by the epoxidation of Narachidonoyl-dopamine (NADA) and N-arachidonoyl serotonin (NA5HT) by cytochrome P450 (CYP) epoxygenases. These epoxides (epoNADA and epoNA5HT) are dual-functional rheostat modulators (varying strength of agonism or antagonism) of the eCB-TRPV1 axis. In fact, epoNADA is a 6-fold stronger agonist of TRPV1 than NADA while epoNA5HT is a 30-fold stronger antagonist of TRPV1 than NA5HT and displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. The epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1β, TNF-α and nitrous oxide (NO) and raise anti-inflammatory IL-10 in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of another eCB, anandamide (AEA). We provide evidence for the direct biochemical mechanism of this potentiation using human CYP2J2, a CYP epoxygenase in the human brain, using detailed kinetics studies and molecular dynamics simulations. Taken all together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by CYP epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are more potent, multi-faceted endogenous molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors. The identification of these molecules will serve as templates for the synthesis of new multi-target therapeutics for the treatment of inflammatory pain.

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Endocannabinoid metabolism by cytochrome P450 monooxygenases

Cited by 50 publications

References 191 publications

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

Interplay Between n‐3 and n‐6 Long‐Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

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