Endocannabinoid Oxygenation by Cyclooxygenases, Lipoxygenases, and Cytochromes P450: Cross-Talk between the Eicosanoid and Endocannabinoid Signaling Pathways

The discovery of the cannabinoid receptors CB1 and CB2 in 19881,2 and 1990,(3) respectively, and of the endogenous cannabinoid ligands (endocannabinoids) arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) in 1992(4) and 1995,(5) respectively, represented major strides in the understanding of cannabinoid physiology and pharmacology. The realization that both endocannabinoids are derivatives of arachidonic acid (AA) also revealed a potential interrelationship between the endocannabinoid and eicosanoid signaling systems that is just beginning to be unraveled. In this review, we explore what is known about the interplay between the two lipid signaling networks and discuss the challenges and opportunities offered by this new field of inquiry. 1.1. Eicosanoid Biosynthetic Pathways AA is an ω-6 tetraunsaturated fatty acid that is a component of mammalian cell membrane phospholipids, where it is predominantly esterified at the sn-2 position. AA’s role in eicosanoid signaling was first discovered in 1964, when Van Dorp et al. and Bergstrom et al. showed that incubation of the radiolabeled fatty acid with bull seminal vesicles led to the formation of prostaglandin E2 (PGE2).6,7 Since that time, we have come to appreciate that a wide range of stimuli (depending on cell type, tissue context, and physiologic state) can trigger the activation of cytosolic phospholipase A2 (cPLA2) and/or other phospholipases, leading to the release of free AA from phospholipid pools. The free fatty acid is then subject to oxidative metabolism by cyclooxygenase 1 and/or 2 (COX-1 and/or COX-2), leading to the formation of the endoperoxide PGH2. Tissue-specific metabolism of PGH2 by a group of PG synthases yields the biologically active PGs (PGE2, PGD2, PGF2α), prostacyclin (PGI2), and thromboxane A2 (TxA2) (Figure ​(Figure11a).8,9 Alternatively, free AA may be metabolized by one of a variety of lipoxygenases (LOXs) that catalyze regio- and stereospecific oxygenation, yielding hydro-peroxyeicosatetraenoic acids (HPETEs). These compounds are enzymatically or chemically reduced to the corresponding hydroxy-eicosatetraenoic acids (HETEs) or undergo further metabolism. Multiple lipoxygenations produce the lipoxins,(10) or in the case of 5-HPETE, epoxidation followed by hydrolysis or glutathione adduction yields the leukotrienes (LTs)9,11 (Figure ​(Figure1b).1b). Finally, free AA may be oxidized at each of its double bonds or at the ω-terminus by cytochromes P450, leading to the epoxyeicosatrienoic acids (EETs) or HETEs(12) (Figure ​(Figure1c).1c). Members of each of these classes of compounds possess a unique range of biological activities. Figure 1 (a) Cyclooxygenase pathway of AA metabolism. AA is converted to PGG2 at the cyclooxygenase active site of COX-1 or COX-2 and is then reduced to PGH2 at the peroxidase active site. PGH2 spontaneously decomposes to yield PGE2 or PGD2, but these compounds, ...