Metabolism of anandamide into eoxamides by 15-lipoxygenase-1 and glutathione transferases.
Human 15-lipoxygenase-1 (15-LO-1) can metabolize arachidonic acid (ARA) into pro-inflammatory mediators such as the eoxins, 15-hydroperoxyeicosatetraenoic acid (HPETE), and 15-hydroxyeicosatetraenoyl-phosphatidylethanolamine. We have in this study investigated the formation of various lipid hydroperoxide by either purified 15-LO-1 or in the Hodgkin lymphoma cell line L1236, which contain abundant amount of 15-LO-1. Both purified 15-LO-1 and L1236 cells produced lipid hydroperoxides more efficiently when anandamide (AEA) or 2-arachidonoyl-glycerol ester was used as substrate than with ARA. Furthermore, L1236 cells converted AEA to a novel class of cysteinyl-containing metabolites. Based on RP-HPLC, mass spectrometry and comparison to synthetic products, these metabolites were identified as the ethanolamide of the eoxin (EX) C(4) and EXD(4). By using the epoxide EXA(4)-ethanol amide, it was also found that platelets have the capacity to produce the ethanolamide of EXC(4) and EXD(4). We suggest that the ethanolamides of the eoxins should be referred to as eoxamides, in analogy to the ethanolamides of prostaglandins which are named prostamides. The metabolism of AEA into eoxamides might engender molecules with novel biological effects. Alternatively, it might represent a new mechanism for the termination of AEA signalling.
Orexo AB, Uppsala, Sweden. Pontus.Forsell@astrazeneca.com
Pontus K A
PK
Forsell
Asa
A
Brunnström
Malin
M
Johannesson
Hans-Erik
HE
Claesson
D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism*; D045744:Cell Line, Tumor; D063388:Endocannabinoids / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D006689:Hodgkin Disease / Q000378:metabolism; D006801:Humans; D017998:Leukotriene D4 / Q000031:analogs & derivatives / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis; D008084:Lipoxygenase / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism*
C531123:14-cysteinylglycyl-15-hydroxy-5,8,10,12-eicosatetraenoic acid; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D015289:Leukotrienes; D053284:Polyunsaturated Alkamides; C526311:eoxin C4; D017998:Leukotriene D4; C094503:glyceryl 2-arachidonate; D008084:Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D005982:Glutathione Transferase; C078814:anandamide