n-3 fatty acids and cysteinyl-leukotriene formation in humans in vitro, ex vivo, and in vivo

Abstract

In humans, dietary n-3 fatty acids ameliorate some chronic inflammatory diseases. In contrast, however, dietary n-3 fatty acids had no effect in patients with bronchial asthma. In bronchial asthma, the cysteinyl-leukotrienes C4, D4, and E4, formed from arachidonic acid, are considered important mediators. They are as vasoconstrictive and bronchoconstrictive as leukotrienes C5, D5, and E5, cysteinyl-leukotrienes derived from eicosapentaenoic acid. Whether and how n-3 fatty acids affect human cysteinyl-leukotriene metabolism is largely unknown. We therefore investigated human cysteinyl-leukotriene metabolism in vitro, ex vivo, and in vivo in the absence and presence of dietary n-3 fatty acids. We demonstrate formation of leukotrienes C5, D5, and E5 from eicosapentaenoic acid in vitro and ex vivo in stimulated human granulocytes. Proof of formation relies on cochromatography with authentic standards on reverse-phase high-performance liquid chromatography, ultraviolet-absorbance spectra, and radioactive tracer studies. In vitro, amounts of leukotrienes C5, D5, and E5 formed depended on the amount of exogenous eicosapentaenoic acid; leukotrienes C4, D4, and E4 formed from endogenous arachidonic acid, however, remained unaltered. A randomized, controlled, observer-blind study in 14 human volunteers, seven of whom supplemented their diet with 7 gm/day of an 85% n-3 fatty acid concentrate for 6 weeks was subsequently performed. Ex vivo, levels of leukotriene E5 almost equaled those of leukotriene E4. Moreover, urinary excretion of leukotriene E4 was assessed to estimate formation of cysteinyl leukotrienes from arachidonic acid in vivo. Urinary excretion of leukotriene E4 was reduced by 35% after dietary supplementation with n-3 fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)