Abstract
Beneficial physiological effects of long-chain n-3 polyunsaturated fatty acids are widely accepted but the mechanism(s) by which these fatty acids act remains unclear. Herein, we report the presence, distribution, and regulation of the levels of n-3 epoxy-fatty acids by soluble epoxide hydrolase (sEH) and a direct antinociceptive role of n-3 epoxy-fatty acids, specifically those originating from docosahexaenoic acid (DHA). The monoepoxides of the C18:1 to C22:6 fatty acids in both the n-6 and n-3 series were prepared and the individual regioisomers purified. The kinetic constants of the hydrolysis of the pure regioisomers by sEH were measured. Surprisingly, the best substrates are the mid-chain DHA epoxides. We also demonstrate that the DHA epoxides are present in considerable amounts in the rat central nervous system. Furthermore, using an animal model of pain associated with inflammation, we show that DHA epoxides, but neither the parent fatty acid nor the corresponding diols, selectively modulate nociceptive pathophysiology. Our findings support an important function of epoxy-fatty acids in the n-3 series in modulating nociceptive signaling. Consequently, the DHA and eicosapentaenoic acid epoxides may be responsible for some of the beneficial effects associated with dietary n-3 fatty acid intake.
Highlights
Beneficial physiological effects of long-chain n-3 polyunsaturated fatty acids are widely accepted but the mechanism(s) by which these fatty acids act remains unclear
Several studies established that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can be oxygenated by cytochrome P450 (CYP) enzymes in a manner parallel to oxygenation of arachidonic acid [5, 14,15,16,17]
Except for the 7,8-EpDPE, which was present in relatively high quantity compared with the other epoxy-fatty acids, the EpETEs in the central nervous system (CNS) were in similar quantities to the EET regioisomers (Table 1)
Summary
Beneficial physiological effects of long-chain n-3 polyunsaturated fatty acids are widely accepted but the mechanism(s) by which these fatty acids act remains unclear. Using an animal model of pain associated with inflammation, we show that DHA epoxides, but neither the parent fatty acid nor the corresponding diols, selectively modulate nociceptive pathophysiology. The DHA and eicosapentaenoic acid epoxides may be responsible for some of the beneficial effects associated with dietary n-3 fatty acid intake.— Morisseau, C., B. A number of beneficial physiological effects have been attributed to dietary n-3 fatty acids including decreasing. Hepatic and renal cytochrome P-450 epoxygenases react well with EPA, DHA, and ARA to yield, respectively, multiple epoxyeicosatetraenoic (EpETE), epoxydocosapentaenoic (EpDPE), and epoxyeicosatrienoic (EET) acid regioisomers [5, 13,14,15,16,17]. In vitro, the EETs, EpDPE, and EpETE inhibit platelet aggregation at concentrations below those affecting thromboxane synthesis [24], suggesting that these natural oxiranes have strong, selective, and possibly specific bioactivities
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have