A cytochrome P450 metabolite of 2-AG
2-Arachidonoyl glycerol (2-AG) is an endogenous central cannabinoid (CB1) receptor agonist that is present at relatively high levels in the central nervous system. 2-AG is hydrolyzed by the enzyme monoacylglycerol lipase, terminating its biological activity, and metabolism by cyclooxygenase-2 and lipoxygenases has been documented. The related endocannabinoid, 2-arachidonoyl ethanolamide (AEA), can be metabolized by cytochrome P450 (CYP450) enzymes in human liver and kidney to a number of epoxy-ethanolamide derivatives. (±)2-(14,15-Epoxyeicosatrienoyl) Glycerol ((±)2-14,15-EG) is a novel CYP450 metabolite of 2-AG in the kidney. (±)2-14,15-EG is a potent mitogen for renal epithelial cells, increasing DNA synthesis in LLCPKcl4 cells at concentrations as low as 100 nM and doubling cell proliferation rates at 1 µM. In these cells, (±)2-14,15-EG activates the metalloprotease ADAM17, which cleaves proTGF-α and releases TGF-α as a ligand that initiates the EGFR-ERK signalling pathway.
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