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Prostaglandins and Other Lipid Mediators

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Endocannabinoid metabolism by cytochrome P450 monooxygenases

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Susan Zelasko a , William R. Arnold b , Aditi Das a,b,c,d,∗ a

Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL 61802, United States Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61802, United States c Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61802, United States d Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61802, United States b

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Article history: Available online xxx

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Keywords: Endocannabinoids Cytochrome P450s Anandamide 2-Arachidonylglycerol Eicosanoids CYP2J2

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The endogenous cannabinoid system was first uncovered following studies of the recreational drug Cannabis sativa. It is now recognized as a vital network of signaling pathways that regulate several physiological processes. Following the initial discovery of the cannabinoid receptors 1 (CB1) and 2 (CB2), activated by Cannabis-derived analogs, many endogenous fatty acids termed “endocannabinoids” are now known to be partial agonists of the CB receptors. At present, the most thoroughly studied endocannabinoid signaling molecules are anandamide (AEA) and 2-arachidonylglycerol (2-AG), which are both derived from arachidonic acid. Both AEA and 2-AG are also substrates for the eicosanoid-synthesizing pathways, namely, certain cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes. In the past, research in the endocannabinoid field focused on the interaction of AEA and 2-AG with the COX and LOX enzymes. Yet, accumulating evidence also points to the involvement of CYPs in modulating endocannabinoid signaling. The focus of this review is to explore the current understanding of CYP-mediated metabolism of endocannabinoids. © 2014 Published by Elsevier Inc.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Discovery of the endocannabinoid signaling system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Endocannabinoid metabolism by eicosanoid-synthesizing enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cytochrome P450 enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Overview of human CYP enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Cytochrome P450 mediated metabolism of AA to form epoxyeicosatrienoic acid (EET) and hydroxyeicosatrienoic acid (HETE) . . . . . . . . . Anandamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Anandamide (AEA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Overview of CYP involvement in AEA metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Anandamide and family 2 CYP epoxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Anandamide and family 4 CYPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Anandamide and polymorphic CYPs (CYP3A4, 2D6, and 2B6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Interaction of the EET-EA and HETE-EAs with the CB receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: 2-AG, 2-arachidonylglycerol; AEA, anandamide; AA, arachidonic acid; CB1 , cannabinoid receptor 1; CB2 , cannabinoid receptor 2; CNS, central nervous system; COX, cyclooxygenase; CYP, cytochrome P450; DAG, diacylglycerol; DHET, dihydroxyeicosatrienoic acid; EGFR, epidermal growth factor receptor; EET, epoxyeicosatrienoic acid; EA, ethanolamine; ERK, extracellular signal-regulated protein kinase; FAAH, fatty acid amide hydrolase; GPCR, G protein coupled receptor; EG, glycerol; HETE, hydroxyeicosatrienoic acid; HEET, hydroxyepoxyeicosatrienoic acid; LOX, lipoxygenase; MAGL, monoacylglycerol lipase; MI, myocardial infarction; NAPE, N-Arachidonylphosphatidylethanolamine; PPAR, peroxisome proliferator-activated receptor; PGH2 , prostaglandin H2 ; TRPV1, vanniloid receptor 1; THC, 9 -tetrahydrocannabinol. ∗ Corresponding author at: Department of Comparative Biosciences, University of Illinois Urbana-Champaign, 3813 Veterinary Medicine Basic Sciences Building, 2001 South Lincoln Avenue, Urbana, IL 61802, United States. Tel.: +1 217 244 0630. E-mail address: [email protected] (A. Das). http://dx.doi.org/10.1016/j.prostaglandins.2014.11.002 1098-8823/© 2014 Published by Elsevier Inc.

Please cite this article in press as: Zelasko S, et al. Endocannabinoid metabolism by cytochrome P450 monooxygenases. Prostaglandins Other Lipid Mediat (2014), http://dx.doi.org/10.1016/j.prostaglandins.2014.11.002

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2-Arachidonylglycerol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. 2-Arachidonylglycerol (2-AG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. CYP-mediated metabolism of 2-AG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Interaction of the 2-EET-EGs with the CB receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocannabinoid hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The endogenous cannabinoid signaling system was first uncovered following studies of the common recreational drug, Cannabis sativa, or marijuana. The psychoactive component of C. sativa, 9 -tetrahydrocanabinol (THC), elicits its activity by binding two cannabinoid receptors: cannabinoid receptor 1 (CB1 ) and 2 (CB2 ) [1–5]. Besides Cannabis-derived analogs, a number of endogenous cannabinoids (endocannabinoids) produced by the body bind to these cannabinoid receptors and elicit similar effects to those typically associated with Cannabis use. The two most thoroughly characterized endocannabinoids are anandamide (AEA) and 2-arachidonylglycerol (2-AG) [6,7]. AEA and 2-AG exhibit neuroprotective, anti-nociceptive, and anti-inflammatory properties that are mediated primarily by CB-receptor-dependent pathways [8,9]. The dysregulation of the endocannabinoid system has been implicated in a wide range of pathologies that include nociception [10,11], emotional disorders [12,13] energy imbalance [14], neurodegenerative diseases [15–19], cancer [20,21], and cardiovascular disease [22–27]. Taken together, these observations provide convincing evidence for the importance of the endocannabinoids in maintaining homeostasis. Therefore, a systematic understanding of all the potential pathways that control endocannabinoid metabolism in the body is crucial for drug development targeted toward this signaling system. In this review, we discuss the cytochrome P450 (CYP) mediated metabolism of endocannabinoids 1.1. Discovery of the endocannabinoid signaling system The discovery of the endocannabinoid system occurred in 1988 following the observation that Cannabis-derived THC inhibits adenylate cyclase activity in neuroblastoma cells. From this came the discovery of a novel G protein-coupled receptor (GPCR) in these cells, which was termed CB1 [28,29]. CB1 is the most abundant GPCR in the central nervous system (CNS) [28–32] with expression in the pre-frontal cortex, hippocampus, substantia nigra, cerebellum, and spinal cord. It is also detectable in cardiac [33], pulmonary [33], intestinal [34], hepatic [35,36], pancreatic [37], and reproductive tissues [33,38,39]. The identification of CB2 followed in 1990, shortly after the discovery of CB1 [40]. CB2 is also a GPCR, but it is expressed primarily in the tonsils, spleen, and immune cells, with the highest levels of expression occurring in B lymphocytes, natural killer cells, and macrophages [33]. There is no clear consensus on the expression of CB2 in the nervous system, but CB2 mRNA and protein has been detected in the brainstem [41]. The role of CB2 in the CNS includes mediation of immunoregulation via microglial cells, which are phenotypically and functionally similar to macrophages [42]. Activation of either CB receptor leads to a myriad of responses that are accompanied by inhibition of adenyl cyclase and attenuation of subsequent pathways [43]. Given the variety of tissue types that express the CB1 and CB2 receptors, the endocannabinoid signaling system has a wide range of physiological implications. These initial studies of CB-receptor activation by the nonendogenous, Cannabis-derived THC molecule piqued the interest

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in researching the endogenous role of the cannabinoid receptors. Following the identification of CB1 and CB2 , the interest in finding the respective endogenous ligands for these receptors grew. Within a few years, the fatty-acid-derived ligands AEA and 2-AG were found to interact with the CB receptors, and upon binding were shown to trigger responses analogous to those observed using non-endogenous THC [44–46]. Overall, the endocannabinoid system is presently known to consist of signaling molecules such as AEA, 2-AG, and other fatty acid compounds that regulate several physiological and cognitive processes in humans via CB1 and CB2 . Besides the cannabinoid receptors, the endocannabinoids AEA and 2-AG also bind to other receptors including certain nuclear peroxisome proliferator-activated receptors (PPAR) [47,48] and, in the case of AEA, the heat-sensing vanniloid type-1 receptor (TRPV1) [49]. 1.2. Endocannabinoid metabolism by eicosanoid-synthesizing enzymes Currently, AEA and 2-AG are the most well studied endocannabinoids. Due to the structural similarity of AEA and 2-AG to the parent molecule arachidonic acid (AA) (Fig. 1) these molecules may also serve as substrates for the eicosanoid-synthesizing enzymes involved in AA metabolism. Eicosanoids are involved in inflammation, cardiovascular diseases, and cancer [50–52]. The generation of eicosanoids from AA occurs through three enzymatic pathways: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 epoxygenase (EPOX). These eicosanoid-generating pathways have been reviewed more thoroughly elsewhere [53]. Both AEA and 2AG are known substrates for certain COX and LOX enzymes and initial studies have demonstrated that these endocannabinoids are also metabolized by specific CYPs. Recently, there has been advances in determining the role of CYPs in endocannabinoid oxidation, particularly with respect to 2-AG metabolism. Additionally, there possibly exists a large degree of cross-talk between the three endocannabinoid-metabolizing pathways therefore novel fattyacid derivatives with presently unknown structures and functions may yet to be discovered [6]. Of the above mentioned eicosanoid-synthesizing pathways, the COX and LOX systems have been thoroughly studied and have been reviewed previously [6,54,55]. Briefly, two COX isoforms are known to oxidize AA to form prostaglandin H2 (PGH2 ), which serves as a precursor for many subsequent pathways. With respect to endocannabinoid metabolism, only the COX-2 isoform converts 2-AG to PGH2 -glycerol (-EG) and converts AEA to PGH2 -ethanolamine (-EA) and PGE2 -EA [55]. COX-2 metabolizes AA, 2-AG, and AEA with similar enzymatic efficiencies [56]. The LOX enzymes typically add an oxygen to AA at C5, C12, and C15 positions [57,58] and various LOX isoforms also metabolize AEA and 2-AG at regioselective positions C12 and C15, with varying degrees of efficiency [59,60,50]. The third route of endocannabinoid metabolism is the CYP pathway, which is an important emerging field within endocannabinoid research. As a whole, the CYPs are a superfamily of hemoproteins that typically monooxygenate a

Please cite this article in press as: Zelasko S, et al. Endocannabinoid metabolism by cytochrome P450 monooxygenases. Prostaglandins Other Lipid Mediat (2014), http://dx.doi.org/10.1016/j.prostaglandins.2014.11.002

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Fig. 1. The formation of AEA and 2-AG and subsequent oxidation by the CYP-mediated pathway. Anandamide (AEA, purple/solid pathway) formation is initiated upon phospholipase A2 (PLA2) releasing arachidonic acid (AA) from the plasma membrane. AA is combined with phophatidylethanolamine (PEA) by N-acyltransferase (NAT) to form N-arachidonyl-phophatidylethanolamine (NAPE), which is finally converted to AEA by N-arachidonyl-phosphatidylethanolamine phospholipase D (NAPE-PLD). In the case of 2-arachidonylglycerol (2-AG, green/dashed pathway), formation is initiated upon, (1) phospholipase C (PLC) producing diacylglycerol (DAG) that is converted to 2-AG by DAG lipase (DAGL), or (2) phospholipase A1 (PLA1) producing 2-AA lysophosphatidic acid (2-AA-LPA) that is converted to 2-AG by lysophospholipase C (lyso-PLC). The cytochrome P450s (CYPs) then oxidize AEA and 2-AG. Single epoxidation reactions with AEA may form any of the four epoxyeicosatrienoic acid ethanolamides (EET-EAs) and the hydroxylation leads to two hydroxyeicosatetraenoic acid ethanolamides (HETE-EAs). Double oxidation reactions with AEA produces hydroxylated epoxyeicosatrienoic acid ethanolamides (HEET-EAs). Hydroxylation of the 5,6- and 14,15-EETs can occur at olefin positions 16, 17, 18, 19 and 20. Oxidation of 2-AG produces 2-epoxyeicosatrienoic acid glycerols (2-EET-EGs). Presently, oxidation has only been shown to occur at the 11,12- and 14,15- positions. Finally, CYP2J2 and CYP2C8 also hydrolyze the ester group in 2-AG and the 2-EET-EGs to either AA or the corresponding EET, respectively, and glycerol.

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variety of endogenous and xenobiotic compounds [51–53]. Evidence supporting the metabolism of AEA and 2-AG by members of the CYP2, -3, and -4 subfamilies continues to accumulate, although further examinations both in vitro and in vivo are needed to understand the full scope of CYP involvement in the endocannabinoid system. This review will focus on the recent advances in the area of CYP-mediated oxidation of AEA and 2-AG as well as the potential physiological implications of the CYP-derived metabolites in this signaling system. The significance of 2-AG is emphasized in this review as recent work has demonstrated it is both a more abundant and potent CB activator [54,61]. Finally, we provide insights on the future directions this research field ought to consider and

pose questions to address the remaining gaps in the present understanding of CYP-mediated endocannabinoid metabolism.

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At present, there are 57 known human CYPs, which are expressed in the liver [56] and in several extrahepatic tissues [57,58] such as the lungs [59], kidneys [60], brain [62], cardiovascular system [63–65], intestinal tissues [66], and platelets [67,68]. In addition, individuals may have polymorphic variants of certain

Please cite this article in press as: Zelasko S, et al. Endocannabinoid metabolism by cytochrome P450 monooxygenases. Prostaglandins Other Lipid Mediat (2014), http://dx.doi.org/10.1016/j.prostaglandins.2014.11.002

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CYP isoforms that significantly alter catalytic efficiency of the enzyme. Polymorphisms in CYPs 2D6, 2C19, and 2C9 account for the most frequent variations in phase I drug metabolism in humans [69]. CYPs typically catalyze the epoxidation, hydroxylation, or, less commonly, the isomerization of endogenous and/or xenobiotic compounds [70]. Many CYPs, especially those concerned with xenobiotic metabolism, promiscuously bind several substrates, allowing for a wide variety of side reactions to occur, which can result in drug-drug interactions [71–73]. A number of CYPs are known to primarily metabolize AA to produce eicosanoid signaling molecules [74–80]. Finally, while the various roles of many CYPs in humans have been elucidated, a handful of orphan CYPs with unknown functions remain, including CYP20A1 of the CNS and members of the CYP4A and 4F subfamilies [81]. Given the variety of CYP functions, the understanding of how each CYP isoform influences the metabolism of endocannabinoids is critical to understand. 2.2. Cytochrome P450 mediated metabolism of AA to form epoxyeicosatrienoic acid (EET) and hydroxyeicosatrienoic acid (HETE) Endocannabinoids (AEA and 2-AG) are derivatives of AA. Therefore, it is useful to consider CYP-mediated metabolism of the endocannabinoids as typically CYPs metabolizes AA to form epoxyeicosatrienoic acids (EETs) [82,83] and hydroxyeicosatrienoic acid (HETE) [83]. Collectively, the EETs mediate inflammation, vascular tone, and angiogenesis that is important in mitigating ischemia and myocardial reperfusion injury [84]. HETEs produced by CYPs are also involved in vasoconstriction and vasodilation [85–87]. Thus far, enzymes in the CYP1, -2, -3, and -4 families have been shown to produce AA metabolites, including CYP2J, 2D, 3A, 4A, and 4F subfamilies in different mammalian species that have been implicated in endocannabinoid metabolism as well [74–80,88]. Epoxygenation reactions are primarily carried out by the CYP2C and 2J families in humans, while CYP4 members have been shown to carry out ␻-20 hydroxylation to form HETEs [89–91]. CYP epoxygenases may form several EET regioisomers that contain R/S enantiomeric forms in varying proportions [92–94] where each possesses specific physiological functions [74,95]. The predominant regioisomers formed by CYPs include 5,6-; 8,9-; 11,12-; and 14,15-EETs, and 12-, 19-, and 20-HETEs [74,96]. Enzymes in the CYP2J subfamily form all four regioisomeric EETs as the major product, as well as 19-HETE [97]. However, the propensity to form these various regio- and stereoisomers is not the same among all CYP isoforms. For instance, CYP2C8 produces only the 14,15and 11,12-EETs in appreciable quantities [98] [99] and 2C9 only produces 14,15-; 11,12-; and 8,9-EET [99]. The CYP4 subfamily, which includes CYP4A11, CYP4A22, and CYP4F isoforms, predominantly produce 20-HETE [78,100]. CYP2D18 from rat only forms the 14,15-; 11,12-; and 8,9-EETs [77]. The eicosanoids formed by CYP metabolism maintain homeostasis in part by regulating blood pressure, inflammation, renal function, immunity, and hemostasis [101]. When formed in excess under pathological conditions, these molecules can contribute to the onset of many acute and chronic diseases. The EET class of molecules is of particular importance in vasculature, renal, and respiratory systems [74,102,103]. The HETE-producing enzymes CYPs 4F and 4A are upregulated in a number of human cancers [100], along with having roles similar to the EET metabolites, e.g. concerning vasculature and hypertension [74]. Additionally, the regioisomers of EETs and HETEs may have different effects even among themselves. The 14,15- and 11,12-EETs promote cell survival of cultured human coronary artery endothelial cells and cultured human lung microvascular endothelial cells, while the 8,9- and 5,6-EET do not [104]. Furthermore, the EETs have been

shown to induce vasodilation in vascular smooth muscle cells [74], although in other cell types certain EETs mediate vasoconstriction by various mechanisms [105–107]. As aforesaid, HETEs can be either vasoconstrictive or vasodilatory depending on the site of release and action [85,86]. Therefore, the EETs and HETEs play an important and opposing role in cell signaling.

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Anandamide (N-arachidonoylethanolamine or AEA) is an endocannabinoid that derives its name from the Sanskrit word “ananda” meaning “joy.” AEA is presently the most thoroughly examined endocannabinoid with respect to metabolism by CYPs and other enzymes, although there are other important endocannabinoid signaling molecules beyond AEA, such as 2-AG. AEA is a highly lipophilic signaling molecule that has a relatively short half-life [93] and is present at low levels ( 14,15-EET-EA > 8,9-EET-EA > 11,12-EETEA > 5,6-EET-EA. Wild type CYP2B6 also produces these four EET-EA metabolites; however, in contrast to CYP2D6 it does not produce significant quantities of 20-HETE-EA. Furthermore, CYP2B6 produces more 11,12-EET-EA and less 14,15-EET-EA than CYP2D6 [118]. Both the biochemical mechanisms and the physiological implications of the CYP-specific metabolite profiles by these, and other CYPs, remain unknown. It should be noted that the observations of CYP2B6 and CYP2D6 metabolizing AEA contradict the kidney and liver studies that show that there is no metabolism of AEA by these enzymes (see Section 3.2) [114]. However, these studies were done using direct assays in vitro with brain samples [118,138] as opposed to the inhibitory antibody screening performed in earlier studies, which may help to explain the discrepancy [114]. Finally, the metabolism of AEA by CYP3A4 also results in the formation of the four EET-EA regioisomers. Based on antibody inhibition in human liver microsomes, it was proposed that a large proportion of hepatic EET-EAs are produced by CYP3A4 though this must be confirmed in vivo [118]. The polymorphic variants of CYP3A4, 2D6, and 2B6 display a range of functionality with respect to AEA metabolism. This may impact the ability of different individuals to produce different levels of endocannabinoid metabolites. Polymorphisms, therefore, ought to be considered in future endocannabinoid research and pharmacologic therapies [140,141,144]. For instance, recent investigation of the common CYP2B6.4 variant indicates it displays higher production of 20-HETE-EA, whereas 2B6.9 only produces the 11,12-EET-EA regioisomer [118]. CYP2D6 exhibits an even higher amount of polymorphism [144] and the CYP2D6.34 variant produces the same AEA metabolites as the wild type isoform, except 5,6-EET-EA that is not formed [118]. The common polymorphism

CYP3A4.4 shows 60% lower production of the four EET-EAs compared to wild-type, but unlike wild type CYP3A4, it uniquely forms the 19-HETE-EA [116]. Hence, certain polymorphic CYPs appear to mediate endocannabinoid signaling through the oxidation of AEA and may account for variation in susceptibility to endocannabinoidrelated pathologies. Additional in vivo investigations are required to better understand the impact of these polymorphisms on endocannabinoid signaling and associated pathologies. 3.6. Interaction of the EET-EA and HETE-EAs with the CB receptors The significance of CYP-mediated metabolism of endocannabinoids such as AEA lies in the resulting physiological consequences of these novel endocannabinoid derivatives. The independent function of AEA signaling at the CB receptors has been reviewed previously [145,146]. It is known, for instance, that prior to oxidative metabolism, AEA mediates analgesia, hypothermia, appetite, and anti-proliferation [147,148]. In regard to CYP expression, AEA has been observed to enhance the expression of CYP3A and CYP2B in rat liver and brain tissue [149,150]. Nevertheless, the precise function of AEA oxidation by the CYP enzymes remains a novel area for detailed study and only a handful of in vivo studies have been performed. Presently, it is known that the EET-EAs and HETEEAs bind to the CB1 and CB2 receptors with different affinities than AEA (Table 2). For instance, the propensity of 5,6-EET-EA binding to CB2 is 1000-fold stronger than AEA [151]. This EET-EA is also slower to degrade than AEA, giving it additional potential to interact with the receptor. The 5,6-EET-EA displays a 300-fold higher binding to the CB2 receptor versus the CB1 receptor, indicating that CYP oxidation may serve as a pathway for CB2 -selective activation that is more robust than AEA [151]. CB2 has been implicated in some of the downstream effects concerning the liver and CNS [112]. For example, CB2 , although not found in normal human liver, was found to be expressed in cirrhotic, hepatic fibrogenic cells and aided in anti-fibrogenesis [152]. The CB2 receptor is also

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upregulated in microglia cells during experimental autoimmune encephalomyelitis in mice [153]. In contrast to the 5,6-EET-EA, the 14,15-EET-EA and 20-HETE-EA appear to bind the CB1 receptor, but with a lower affinity than AEA [118]. Stability assays using rat brain homogenate indicate the 14,15-EET-EA and 20-HETE-EA metabolites also display shorter half-lives compared to AEA, implying that these metabolites are less potent than AEA [118]. Together, these studies suggest that CYP action may alter the physiological fate of AEA as a means for fine-tuned homeostatic regulation. One of many important, unanswered questions is whether the remaining regioisomeric products of CYP-mediated AEA metabolism interact with the CB1 , CB2 , or other receptors. Given the wide and important role AEA plays in maintaining homeostasis, it is critical to better discern how the CYP pathway enhances or diminishes such signals, especially if the endocannabinoid system is to be considered a target of clinical intervention. 4. 2-Arachidonylglycerol 4.1. 2-Arachidonylglycerol (2-AG) Currently, the other well-studied endocannabinoid is 2-AG. 2AG is derived from the commonly distributed pre-cursor molecule diacylglycerol (DAG) that bears an AA at the 2-position [7]. It has also been proposed that 2-AG can be synthesized by dephosphorylation of arachidonoyl-lysophosphatic acid (LPA) by lysophospholipase C [154,155] (Fig. 1). A more detailed review of 2-AG synthesis and degradation has been previously published [156]. The role of CYP-mediated metabolism of 2-AG has not been a topic of discussion in previous reviews, though accumulating evidence suggests that 2-AG plays a significant role in the CNS signaling. 2-AG and AEA follow different routes of synthesis and degradation that one could speculate would partly account for the specificities of each molecule. Accordingly, the level of 2-AG in the brain was found to be 800 times higher than that of AEA [44,108]. The relative CB1 and CB2 binding capacities of these two endocannabinoids are also different, where 2-AG preferentially binds the most abundant CNS GPCR, namely CB1 [28,29], while AEA is unique in that it activates TRPV1 in addition to CB1 and CB2 [49]. Finally, altering 2-AG metabolism exerts dramatic changes on central synaptic transmission via CB1 with concurrent 2-AG accumulation in CB1 expression regions, whereas alteration of AEA levels does not [15,157–161]. Therefore, while it was once believed that 2-AG and AEA exhibit nearly identical pharmacological properties due to their close structural similarities and potential to activate the same receptors, this notion ought to be reevaluated [1,162–164]. 4.2. CYP-mediated metabolism of 2-AG Within the last few years, CYP-mediated metabolism of 2-AG that enhances binding to CB1 has been demonstrated. With respect to the CYP branch, it is conceivable that CYPs would produce four regioisomeric EET-EGs due to the similarity in structure of 2-AG to AA. However, at present only two regioisomers (2-11,12- and 2-14,15-EET-EG) have been isolated from renal epithelial cells, while the 2-8,9- and 2-5,6-EET-EGs were not detected in these tissues [54]. Surprisingly, early studies showed the 2-AG is not metabolized by rat liver and kidney microsomes that express the highest levels of CYPs, nor is it oxidized by recombinant CYP2C8 (human), CYP2C11 (rat), and CYP2C23 (rat), which are known to epoxygenate AA [54]. However, our recent work shows that upon incubation of 2-AG with CYP2J2, the 2-11,12- and 2-14,15-EET-EG regioisomers are produced in vitro [61]. These 2-EET-EGs display tighter binding to CB1 as compared to 2-AG [54]. Consequentially,

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the cardiovascular epoxygenase CYP2J2 remains the only CYP shown to metabolize 2-AG (Table 1). Structure-function studies may help determine why the traditional CYP2C epoxygenases do not oxidize 2-AG, while CYP2J2 does. Considering that AEA is metabolized by CYPs not typically considered as epoxygenases (e.g. CYP2D6), it may be worth evaluating such CYPs in 2-AG metabolism as well. Finally, if not by CYPs, these EET-EGs may form by other means. As Chen and coworkers speculate, the formation of the 2-EET-EGs may also be possible by cleaving EET glycerophospholipids via PLC and diacylglycerol lipase and/or by hydrolysis of EET phospholipids via PLA1 and lysophospholipase C [54]. 4.3. Interaction of the 2-EET-EGs with the CB receptors The compound 2-AG and its physiological consequences have been studied and reviewed previously [146,147,165], but the implications of the CYP-mediated metabolites have only recently begun to be elucidated. The two aforementioned metabolites of 2-AG (2-11,12-EET-EG and 2-14,15-EET-EG) have been isolated directly from physiological sources, which corroborates the observed formation of these metabolites by either CYP-mediated or other alternate pathways [54]. Yet, the precise role of these oxidized products remains unclear [54]. Initial insights into the metabolite functions show that both the 2-11,12- and 2-14,15-EET-EGs bind rat brain extracts overexpressing CB1 with Ki values of 23 ± 3 nM and 40 ± 5 nM, respectively [54] (Table 2). Both metabolites also bind rat spleen extracts overexpressing CB2 receptors with Ki values of 75 ± 6 nM and 138 ± 9 nM for the 2-11,12-, and 2-14,15EET-EGs, respectively [54] (Table 2). From these results, it would appear that the 2-11,12-EET-EG is a more potent agonist for the two CB receptors overall and that 2-AG metabolites favor CB1 binding. Additionally, the affinities of the metabolites for the CB receptors appear to be higher than 2-AG itself for either receptor [54]. Therefore, the CYP oxidized metabolites of 2-AG would be expected to constitute a bioactivation of the CB1 receptor. This appears to contrast with AEA derived 5,6-EET-EA that preferentially binds the CB2 receptor with higher affinity than AEA. Note that 2-AG itself shows a higher affinity for the CB receptors than AEA. This evidence suggests a hierarchy of binding capacities among 2-AG, AEA, and their oxidized metabolites where the EET-EGs bind the tightest among these three. Our studies indicate CYP2J2, which is primarily present in cardiovascular structures, metabolizes 2-AG to form 2-11,12-EETEG and 2-14,15-EET-EG (Table 1). Furthermore, 2-AG levels are present at reasonable levels in the heart (3.25 ± 1.15 nmol/g tissue [169], compared to 3.36 ± 1.34 in the brain from rat models [168]) and platelets [171], suggesting a need for 2-AG signaling in this organ. A potential role for 2-AG and its oxidized metabolites is cardiovascular CB1 signaling is following acute tissue damage. In experimental rat models of acute myocardial infarction (MI), blocking CB1 with the specific antagonist SR141716A increased endothelial dysfunction, decreased post-MI hypotension, and led to overall worse mortality rates [171]. Blocking the shock-related hypotension attributed to CB1 signaling had a detrimental effect on early rat survival. This is in agreement with the finding that post-MI restoration of blood pressure alone is not beneficial, as illustrated by the persistent high mortality rate in patients given high doses of vasoconstricting catecholamines [171]. The ability of 2-AG and/or the 2-EET-EGs to act as vasodilators via CB1 suggests a role in minimizing acute tissue damage by mediating vascular tone and endothelial function [171]. Additionally, there have been initial studies with hydrolysisresistant ether analogs of the two 2-EET-EGs that were shown to activate p44/p42 extracellular signal-regulated kinase pathways in Chinese hamster ovary cell lines expressing both of the human CB receptors [54]. The 2-EET-EGs were also shown to activate

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N18TG2 neuroblastoma cells that only express CB1 and promyelocytic leukemia HL-60 cells that only express CB2 receptors [54]. The interaction of the 2-14,15-EET-EG has been further characterized using a renal proximal tubule epithelial cell line and was shown to activate epidermal growth factor receptor (EGFR) signaling that which aids renal cell recovery, whereas 2-AG alone exerts no effect [166]. Interestingly, the AA-derived 14,15-EET also activates EGFR signaling via heparin-binding EGF-like growth factor, while 214,15-EET-EG does so using transforming growth factor ␣ (TGF␣) [166,167]. Both eicosanoids are, therefore, implicated in the regulation of various stages of renal cell injury recovery and do so using separate pathways. Together, this demonstrates a possible physiological activation pathway for the oxidized 2-AG metabolites. Further evidence from mouse model studies show that both 2-11,12- and 2-14,15-EET-EG analogs induce a significant decrease in locomotor activity as well as a hypothermic response, which corroborates the physiological role of endocannabinoid activity [54]. The analogs have also been shown to induce a CB1 -dependent vasorelaxing response in renal glomerular afferent arterioles and a CB2 -dependent neutrophil-like chemotaxis of HL-60 cells [54]. Together, these results highlight the importance CYP-mediated metabolism of 2-AG and the physiological roles of these metabolites; however, further studies are needed to clearly elucidate other unknown physiological effects particularly in the CNS and cardiovasculature.

5. Endocannabinoid hydrolysis The endocannabinoids undergo inactivation through hydrolysis by specific enzymes. Fatty acid amide hydrolase (FAAH) carries out the hydrolytic cleavage of AEA to form AA and ethanolamine. This integral membrane enzyme is expressed mostly in the liver and brain, as well as the intestines, spleen, and lungs [173]. Evidence for the role of FAAH in inactivating AEA stems from in vivo experiments that demonstrate, in the absence or inhibition of FAAH, cells rapidly succumb to necrosis after AEA treatment [174]. N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is also capable of inactivating AEA [175]. The hydrolysis of 2-AG to AA and glycerol is carried out primarily by monoacylglycerol lipase (MAGL), although a minor percentage of 2-AG is also hydrolyzed by FAAH [176] and serine lipases ␣–␤ hydrolase domains 6 and 12 (ABHD6, ABHD12) [165,177]. Expression of MAGL occurs in the brain, adipose tissue, intestines, and pancreatic islet cells [165,178–180]. The inactivation of AEA and 2-AG plays a necessary role in attenuating endocannabinoid signaling. In addition to FAAH- and MAGL-mediated hydrolysis, alternative routes of endocannabinoid inactivation have been elucidated. For instance, it has been shown that the cleavage of the ester bond in 2-AG into free AA and glycerol occurs in vitro using incubations of either CYP2J2 or CYP2C8 with NADPH and cytochrome P450 reductase [61]. The AA formed in this process can then be converted into signaling molecules EETs and HETEs that are essential to mediating cardiovascular homeostasis. This was the first evidence of CYP-mediated inactivation of 2-AG, although previously CYPs have been shown to cleave ester bonds [70]. In tissues where CYP concentrations are higher, this may become a predominant mechanism of 2-AG inactivation and could also explain why 2-AG epoxides were not detected in liver microsomes incubations. These findings provide a groundwork by which further studies may be stimulated. In regards to the CYP-generated metabolites of AEA and 2AG, the epoxygenated EET-EGs and EET-EAs undergo secondary metabolism that involves epoxide ring opening. Epoxide hydrolysis has been previously demonstrated in EETs derived from AA using microsomal and soluble epoxide hydrolases that catalyze

the addition of water to epoxides, forming the corresponding dihydroxyeicosatrienoic acids (DHETs) [181,182]. The inhibition of epoxide hydrolase has been shown to elevate levels of EETs [181]. In a similar fashion, the four EET-EAs have been shown to form DHET-EAs via secondary metabolism by epoxide hydrolase [114]. For instance, the 5,6-EET-EA is degraded by epoxide hydrolase in mouse brain homogenate with a half-life of 32 min (though it does not completely disappear) [151], whereas AEA is entirely hydrolyzed (presumably by FAAH) in 14 min. The physiological relevance of the produced DHET-EAs and putative DHET-EGs remains unclear. Furthermore, the degradation of AEA and 2-AG by additional enzymatic routes remains to be investigated.

6. Concluding remarks Since the initial discovery of the endogenous cannabinoid receptors, CB1 and CB2 , substantial progress has been made in characterizing the biochemical and physiological properties of the endocannabinoid system. Thus far, the most thoroughly studied components of this signaling network remain the two cannabinoid receptors, CB1 and CB2 , as well as the lipid signaling molecules AEA and 2-AG. The biological activity of AEA and 2-AG may be altered by eicosanoid synthesizing enzymes in the COX, LOX, and CYP pathway. The involvement of certain CYP enzymes in oxidizing AEA and 2-AG was demonstrated within the last few years. The CYPs add a level of fine-tuned modulation to the endocannabinoid system that attenuates or enhances the capacity of AEA and 2-AG to act as signaling molecules. Several CYPs have been shown to form four AEA and two 2-AG epoxide derivatives. A number of CYPs are also known to produce hydroxylated AEA and 2-AG derivatives. Each modification of the endocannabinoid molecules represents a potential alteration in binding capacity to the target receptors, which has been observed for certain metabolites as mentioned in Sections 3.6 and 4.3. Additionally, CYP2J2 and CYP2C8 are involved in the inactivation of 2-AG that may influence the bioavailability of this key non-classical neurotransmitter. While it is clear that CYP enzymes play a significant role in the metabolism of AEA and 2-AG, there remain many potential avenues of study that will provide a more complete understanding of how CYPs influence the endocannabinoid system, or vice versa. For instance, the physiological role of the EET-EAs, HETE-EAs, and 2-EET-EGs in activating or attenuating endocannabinoid signaling requires further attention. The inactivation mechanisms of the endocannabinoid molecules by the remaining human CYPs beyond those enzymes described in Sections 3 and 4 should be evaluated. There are several CYPs isoforms that metabolize AA in the CYP1A, 2B, 2C, 2E, 2J, 2D, 2N, 4A, and 4F families, which have not yet been evaluated for endocannabinoid metabolism. Furthermore, the CYPs previously evaluated for endocannabinoid oxidation ought to be revisited in light of the new discovery that CYP2J2 and 2C8 to induce 2-AG cleavage. Another potentially useful route of study may be the orphan CYPs, considering that the previously orphaned CYP4X1 was shown to metabolize AEA [81,126]. The remaining orphan CYPs include CYP2A7, 2S1, 2U1, 2W1, 3A43, 4A22, 4F11, 4F22, 4V2, 4Z1, 20A1, and 27C1. Additionally, several endocannabinoids beyond AEA and 2-AG have been recognized, which include 1-arachidonylglycerol, noladin ether [186], virodhamine [187], N-arachidonyl dopamine [188], N-arachidonylglycine [189], and oleamide [190]. The metabolism of these endogenous molecules by CYP isoforms should be considered to better understand their role within the endocannabinoid system. Overall, CYP involvement in the endocannabinoid system remains a relatively new field that requires further study to fully elucidate and understand the physiological and pharmacological relevance. As CYPs perform numerous functions on a myriad of substrates, including xenobiotic

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metabolism, investigations in the participation of this pathway in the endocannabinoid system ought to provide intriguing results that will aid in the development of therapeutics. 7. Uncited references [170,172,183–185,191–201]. Acknowledgements

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We sincerely thank Mr. Daniel McDougle for providing insights and editing this manuscript. In this review, we have tried our best to 700 review the current knowledge of this field. However, there are sev701 702 eral new findings related to the receptors and metabolites of AEA, 703 2-AG, and other endocannabinoids that are beyond the scope of 704 this review. We thank the American Heart Association and Molec705 ular and Cellular Biology summer fellowship for supporting Ms. 706 Q4 Susan Zelasko’s summer research. We thank UIUC start-up funds, 707 Research Board grant, and private funding to Dr. Das for supporting 708 the research. 699

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Endocannabinoid metabolism by cytochrome P450 monooxygenases.

The endogenous cannabinoid system was first uncovered following studies of the recreational drug Cannabis sativa. It is now recognized as a vital netw...
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