Chem. 278, 14677-14687). Our objective was to determine whether similar derivatives are enzymatically synthesized from other C-22 fatty acids and whether these molecules possess inflammation resolution properties. The reaction of DHA, DPAn-3, and DPAn-6 with 5-, 12-, and 15-lipoxygenases produced oxylipins, which were identified and characterized by liquid chromatography coupled with tandem mass-spectrometry. DPAn-6 and DPAn-3 proved to be good substrates for 15-lipoxygenase. 15-Lipoxygenase proved to be the most efficient enzyme of the three tested for conversion of long chain polyunsaturated fatty acids to corresponding oxylipins. Since DPAn-6 is a major component of Martek DHA-S TM oil, we focused our attention on reaction products obtained from the DPAn-6 and 15-lipoxygenase reaction. (17S)-hydroxy-DPAn-6 and (10,17S)-dihydroxy-DPAn-6 were the main products of this reaction. These compounds were purified by preparatory high performance liquid chromatography techniques and further characterized by NMR, UV spectrophotometry, and tandem mass spectrometry. We tested both compounds in two animal models of acute inflammation and demonstrated that both compounds are potent anti-inflammatory agents that are active on local intravenous as well as oral administration. These oxygenated DPAn-6 compounds can thus be categorized as a new class of DPAn-6-derived resolvins.
Background: The resolution of inflammation is an active process mediated by endogenous lipids formed by lipoxygenases and cyclo-oxygenases at the site of inflammation. Enzymatically oxygenated derivatives (oxylipins) of the omega-3 fatty acids DHA and EPA (resolvins) have potent resolution activity. Objectives: To determine if oxylipins are enzymatically synthesized from the omega-6 fatty acid DPAn-6 and whether these molecules possess pro-resolution, anti-inflammatory properties. Results: Two major metabolites, 17-hydroxy-DPAn-6 and 10,17-dihydroxy-DPAn-6, were formed from DPAn-6 following reaction with soybean 15-lipoxygenase. The identity of these metabolites was confirmed by LC/MS/MS, NMR, and UV analysis. 17-hydroxy-DPAn-6 was also formed following incubation of DPAn-6 with whole human blood. In a mouse air pouch model of acute inflammation, local administration of 100 ng (0.005 mg/kg) of either 17-hydroxy-DPAn-6 or 10,17-dihydroxy DPAn-6 resulted in 70–80% reduction in leukocyte trafficking, comparable to that observed following indomethacin (5 mg/kg ip) administration. The anti-inflammatory activity of both compounds was confirmed in a rat hind paw edema model of acute inflammation. Intravenous administration of 5 μg (~0.025 mg/ml) of either compound resulted in ~25% reduction in paw edema post carrageenan challenge. Both DPAn-6 oxylipins were also active in the hind paw model after oral administration. Conclusions: Oxylipins derived from DPAn-6 are natural compounds possessing potent anti-inflammatory activity. These compounds or analogs thereof are candidates for new drugs that act uniquely to resolve inflammation.
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