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

These results suggested that the PGE and PGF synthases both accept PGH2-G and PGH2-EA as substrates, a conclusion that was confirmed for PGE synthase through incubation of the recombinant microsomal enzyme with 2-AG in the presence of COX-2

Carol A. Rouzer

2011

Scholarcy highlights

  • The ethanolamide and glyceryl ester of PGH2 produced from the metabolism of AEA and 2-AG, respectively, are converted to the same range of eicosanoid products as PGH2 with the exception of the TXA2 analogue. Lipoxygenase pathway of AA metabolism
  • AA is converted by LOX enzymes to position-specific HPETEs, which are reduced to the corresponding HETEs. 5-LOX converts 5-HPETE to LTA4, which may be metabolized to LTB4 or LTC4
  • LOX or 12-LOX. Cytochromes P450 catalyze the epoxygenation of AA at each of the double bonds, producing the range of products shown
  • Incubation of HCA-7 cells with 2-AG resulted in the formation of PGE2-G and PGF2α-G, while incubation with AEA resulted in the corresponding ethanolamides. These results suggested that the PGE and PGF synthases both accept PGH2-G and PGH2-EA as substrates, a conclusion that was confirmed for PGE synthase through incubation of the recombinant microsomal enzyme with 2-AG in the presence of COX-2
  • Fowler and Tiger showed that PGD2-G, PGE2-G, and PGF2α-G did not block the hydrolysis of AEA or 2-oleoylglycerol by cytosolic and membrane fractions from rat brain homogenates, and Matias et al showed that PGD2-EA, PGE2-EA, and PGF2α-EA did not block AEA hydrolytic activity in N18TG2 cell membranes, which are rich in Fatty acid amide hydrolase. These results suggest that PG-Gs and PG-EAs do not interact with FAAH or MAG lipase. This conclusion was further supported by Vila et al, who showed that PG-Gs are poor substrates for purified FAAH and MAG lipase and that specific inhibitors of these enzymes only partially blocked the hydrolysis of PGE2-G in RAW264.7 cells and dog brain homogenates
  • There is an extensive literature on the pharmacology of PGF2α-EA, indicating that it does not interact with the FP receptor. Considering the fact that oxygenated endocannabinoids are usually present at much lower levels than free acid eicosanoids in vivo, it is highly unlikely that these compounds can successfully compete for binding to the traditional prostanoid receptors

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