Selective oxygenation of the endocannabinoid 2-arachidonylglycerol by leukocyte-type 12-lipoxygenase.

Moody JS, Kozak KR, Ji C, Marnett LJ
Biochemistry. 2001 40 (4): 861-6

PMID: 11170406 · DOI:10.1021/bi002303b

The endogenous cannabinoid system appears to serve vascular, neurological, immunological, and reproductive functions. The identification of 2-arachidonylglycerol (2-AG) as an endogenous ligand for the central (CB1) and peripheral (CB2) cannabinoid receptors has prompted interest in enzymes capable of modifying or inactivating this endocannabinoid. Porcine leukocyte 12-liopoxygenase (12-LOX) oxygenated 2-AG to the 2-glyceryl ester of 12(S)-hydroperoxyeicosa-5,8,10,14-tetraenoic acid (12-HPETE-G). The k(cat)/K(M) for oxygenation of 2-AG was 40% of the value for arachidonic acid. In contrast to the results with leukocyte 12-LOX, 2-AG oxygenation was not detected with platelet-type 12-LOX. Among a series of structurally related arachidonyl esters, 2-AG served as the preferential substrate for leukocyte 12-LOX. 12(S)-Hydroxyeicosa-5,8,10,14-tetraenoic acid glyceryl ester (12-HETE-G) was produced following addition of 2-AG to COS-7 cells transiently transfected with leukocyte 12-LOX. These results demonstrate that leukocyte-type 12-LOX efficiently oxidizes 2-AG in vitro and in intact cells, suggesting a role for this oxygenase in the endogenous cannabinoid system.

MeSH Terms (18)

Animals Arachidonate 12-Lipoxygenase Arachidonic Acids Blood Platelets Cannabinoid Receptor Modulators Cannabinoids Chromatography, Liquid COS Cells Endocannabinoids Glycerides Humans Kinetics Leukocytes Lipid Peroxidation Mass Spectrometry Spectrophotometry, Ultraviolet Swine Transfection

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