FIG. 3.

Catabolism of AEA and 2-AG. The degradation of AEA is driven by the membrane-linked fatty acid amide hydrolase (FAAH) yielding arachidonic acid and glycerol. Then, arachidonic acid can be converted to prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids (HETEs) or epoxyeicosatrienoic acids (EETs) by COXs, LOXs, and by the microsomal cytochrome P450 system, respectively. On the other hand, AEA might be metabolized by cyclooxygenase-2 (COX-2), lipoxygenases (LOXs), or the members of the CYP 450 as well, yielding different AEA derivatives such as prostaglandin ethanolamine esters, hydroxyeicosatetraenoic ethanolamines (HETE-EAs), or epoxyeicosatrienoic ethanolamines (EET-EAs), respectively. Monoacylglycerol lipase (MAGL) is the key enzyme in the conversion of 2-AG to arachidonic acid and glycerol, although other enzymes are thought to be involved in the degradation of 2-AG such as the α/β hydrolase domains 6 and 12 (Abhd6 and Abhd12, respectively). Similarly to AEA, 2-AG may serve as a substrate for COX-2, for LOXs, and for microsomal cytochrome P450 enzymes (CYP 450) as well, yielding prostaglandin glycerol esters, hydroxyeicosatetraenoic glycerol (HETE-Gs), or epoxyeicosatrienoic glycerol (EET-Gs) derivatives, respectively. Thus, the degradation of endocannabinoids indirectly contributes to the formation of proinflammatory mediators. The most common catabolic pathways are highlighted by thick arrows. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars