Department of Entomology and Cancer Center, School of Medicine, University of California, Davis, CA 95616, USA.
J Lipid Res. 2010 Dec;51(12):3481-90. doi: 10.1194/jlr.M006007. Epub 2010 Jul 27.
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.
长链 n-3 多不饱和脂肪酸具有有益的生理作用，这已得到广泛认可，但这些脂肪酸的作用机制尚不清楚。本文报道了可溶性环氧化物水解酶（sEH）对 n-3 环氧脂肪酸的存在、分布和水平的调节，以及 n-3 环氧脂肪酸（特别是来源于二十二碳六烯酸（DHA）的环氧脂肪酸）具有直接的镇痛作用。我们制备了 n-6 和 n-3 系列中 C18:1 至 C22:6 脂肪酸的单环氧，并对其各个非对映异构体进行了纯化。通过 sEH 测量了纯非对映异构体水解的动力学常数。令人惊讶的是，最好的底物是中链 DHA 环氧化物。我们还证明 DHA 环氧在大鼠中枢神经系统中含量相当丰富。此外，通过与炎症相关的疼痛动物模型，我们表明 DHA 环氧，而不是母体脂肪酸或相应的二醇，选择性地调节伤害性生理病理学。我们的发现支持 n-3 系列环氧脂肪酸在调节伤害性信号中的重要功能。因此，DHA 和二十碳五烯酸环氧可能是与饮食中 n-3 脂肪酸摄入相关的一些有益作用的原因。
