Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2

Arnold, William R.; Weigle, Austin T.; Das, Aditi

doi:10.1016/j.jinorgbio.2018.03.016

Cited by 43 publications

(45 citation statements)

References 56 publications

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“…In vitro, the major cannabinoids Δ9-tetrahydrocannabinol (THC), CBD, and cannabinol (CBN) were found to either inhibit or induce the cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) through various mechanisms and extents. Specifically, CYP3A4/5/7, CYP2D6, CYP2C9/19, CYP2A6, CYP2B6, CYP1A1/2, CYP1B1, and CYP2J2 were generally inhibited by those cannabinoids (Yamaori et al, 2010(Yamaori et al, , 2011a(Yamaori et al, ,b,c, 2012Jiang et al, 2013;Arnold et al, 2018), whereas CYP2C9 and the mRNA of CYP1A1 were induced by THC (Roth et al, 2001;Bland et al, 2005). As for UGT, UGT1A9 was inhibited by both CBD and CBN, and UGT2B7 was inhibited by CBD but was induced by CBN (Al Saabi et al, 2013).…”

Section: Introductionmentioning

confidence: 97%

In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

2019

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The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to a higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the individual major cannabinoids and metabolites Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-nor-THC-carboxylic acid, and 11-hydroxy-THC on CES1 activity. S9 fractions from human embryonic kidney 293 cells stably expressing CES1 were used in the assessment of cannabinoid inhibitory effects. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitivenoncompetitive mechanism. The inhibition constant (K i ) values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 mM (0.170, 0.306, and 0.0817 mg/ml), respectively. Inhibition potency was increased when THC, CBD, and CBN were combined. Compared with the potential unbound plasma concentrations attainable clinically, the K i values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have a limited impact on CES1. Carefully designed clinical studies are warranted to establish the clinical significance of these in vitro findings.https://doi.org/10.1124/dmd.118.086074.ABBREVIATIONS: AUC, area under the plasma concentration-time curve; CBD, cannabidiol; CBN, cannabinol; CES1, carboxylesterase 1; DDI, drug-drug interaction; [I], inhibitor concentration; I max , maximal degree of inhibition; I max,u , maximal unbound plasma concentration of the inhibitor observed in clinical studies; K i , inhibition constant; LC-MS/MS, liquid chromatography tandem mass spectrometry; OC, oseltamivir carboxylate; 11-OH-THC, 11-hydroxy-Δ9-tetrahydrocannabinol; OST, oseltamivir phosphate; P450, cytochrome P450; R AUC , ratio of the area under plasma concentration-time curve of substrate with the presence of inhibitor over that without; R v , percentage ratio; THC, Δ9-tetrahydrocannabinol; THC-COOH, 11-nor-Δ9-tetrahydrocannabinol-carboxylic acid; UGT, UDP-glucuronosyltransferase.

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Section: Introductionmentioning

confidence: 97%

In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

2019

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“…The MD simulations support that up to three overlapping binding sites are possible, which can help to explain the observed complex AEA and eVD interactions, such as the regioselectivity change in the AEA metabolites ( Figure S29) and the potentiation of eVD metabolism (Figures 3 and 4). We have previously observed complex inhibition and regioselectivity changes for endogenous substrates of CYP2J2 59,96,97 ; however, this is the first report of a potentiation of CYP2J2 metabolism. Due to the poor solubility of the lipid substrates used in these studies, we could not accurately determine the binding constants to understand the cooperative nature of the potentiation.…”

Section: Levels Of Evds In Porcine Brain and Metabolism Of Exogenous mentioning

confidence: 59%

“…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%

“…We next incorporated CYP2J2 and CPR into stable nanoscale lipid bilayers known as Nanodiscs (ND) and proceeded to determine the kinetics of the 14',15'-epoxide formation (Figure 3c). The metabolism of NA5HT by CYP2J2 is in a similar range as the metabolism of AEA and other lipid PUFAs, 59,62 but the metabolism of NADA is low. Interestingly, the data demonstrate the presence of multiple binding sites, as the kinetics plots strongly deviate from a typical Michaelis-Menten model.…”

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confidence: 98%

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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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“…1E and F). 11,67 Based on these findings, O-AEA is a poor substrate for CYP2J2 and might be a potential inhibitor of CYP2J2.…”

Section: Resultsmentioning

confidence: 99%

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

et al. 2018

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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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Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2

Cited by 43 publications

References 56 publications

In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

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

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

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