(±)13(14)epdpa

Cytochrome P450 metabolism of polyunsaturated fatty acids produces numerous bioactive epoxide regioisomers. (±)13(14)-EpDPA is a docosahexaenoic acid epoxygenase metabolite, derived via epoxidation of the 13,14-double bond of DHA. It has been detected in rat brain and spinal cord and is a preferred substrate for soluble epoxide hydrolase with a Km value of 3.2 μM. (±)13(14)-EpDPA demonstrates antihyperalgesic activity in inflammatory and neuropathic pain models. (±)13(14)-EpDPA and other epoxy metabolites of DHA are also reported to potently inhibit angiogenesis and tumor growth in in vitro assays.

EDHF (endothelium-derived hyperpolarizing factor) is an unidentified mediator released from vascular endothelial cells in response to acetylcholine and bradykinin which is distinct from the NOS- (nitric oxide) and COX-derived (prostacyclin) vasodilators.[1],[2]Cytochrome P450 (CYP450) metabolism of polyunsaturated fatty acids produces epoxides such as (±)14(15)-EET which are prime candidates for the actual active mediator.[3] However, the CYP450 metabolites of eicosapentaenoic acid and docosahexaenoic acid have been little studied relative to arachidonate epoxygenase metabolites. (±)16(17)-EpDPA is the DHA homolog of (±)14(15)-EpETrE, derived via epoxidation of the 16,17-double bond of DHA. The EDHF activity of (±)16(17)-EpDPA has not yet been determined. The epoxygenase metabolites of DHA have also been detected in a mouse inflammation model.[4]

19R(20S)-EpDPA is an oxylipin and a metabolite of docosahexaenoic acid .1,2It is formed from DHA by various cytochrome P450 (CYP) isoforms in a stereoselective manner.219R(20S)-EpDPA (30 nM) prevents calcium-induced increases in the spontaneous beating of isolated neonatal rat cardiomyocytes (NRCMs).3 1.Cinelli, M.A., Yang, J., Scharmen, A., et al.Enzymatic synthesis and chemical inversion provide both enantiomers of bioactive epoxydocosapentaenoic acidsJ. Lipid Res.59(11)2237-2252(2018) 2.Lucas, D., Goulitquer, S., Marienhagen, J., et al.Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450J. Lipid Res.51(5)1125-1133(2010) 3.Burke, J.E., and Dennis, E.A.Phospholipase A2 structure/function, mechanism, and signalingJ. Lipid Res.50(Suppl)S237-S242(2009)

Docosahexaenoic acid is the most abundant ω-3 fatty acid in neural tissues, especially in the brain and retina. (±)7(8)-EpDPA is an epoxide derivative of DHA that is generated by the action of cytochrome P450 epoxygenases. It is naturally occurring in plasma and brain and spinal cord tissues and is increased following dietary supplementation with ω-3 fatty acids. (±)7(8)-EpDPA and other epoxy metabolites of DHA modulate receptor and channel activities to evoke diverse effects, such as promoting vasodilation, inhibiting angiogenesis, and decreasing inflammatory and neuropathic pain. (±)7(8)-EpDPA is a substrate of soluble epoxide hydrolase (KM = 15 μM), which converts it to the corresponding diol.

Cytochrome P450 metabolism of polyunsaturated fatty acids produces numerous bioactive epoxide regioisomers. (±)10(11)-EpDPA is a docosahexaenoic acid epoxygenase metabolite, derived via epoxidation of the 10,11-double bond of DHA. It has been detected in rat brain and spinal cord, as well as human serum, and acts as a substrate for soluble epoxide hydrolase with a Km value of 5.1 μM. (±)10(11)-EpDPA and other epoxy metabolites of DHA are reported to demonstrate antihyperalgesic activity in inflammatory and neuropathic pain models and to potently inhibit angiogenesis and tumor growth in in vitro assays.

EDHF (endothelium-derived hyperpolarizing factor) is an unidentified mediator released from vascular endothelial cells in response to acetylcholine and bradykinin which is distinct from the NOS- (nitric oxide) and COX-derived (prostacyclin) vasodilators. Cytochrome P450 (CYP450) metabolism of polyunsaturated fatty acids produces epoxides such as (±)14(15)-EpETrE which are prime candidates for the actual active mediator. However, the CYP450 metabolites of eicosapentaenoic acid and docosahexaenoic acid have been little studied relative to arachidonate epoxygenase metabolites. (±)19(20)-EpDPA is a DHA epoxygenase metabolite, derived via epoxidation of the ω-3 double bond of DHA. The EDHF activity of (±)19(20)-EpDPA has not yet been determined. The epoxygenase metabolites of DHA have also been detected in a mouse inflammation model.