Flaxseed Oil Supplementation Increases Plasma F1-Phytoprostanes in Healthy Men

Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been reported to reduce lipid peroxidation products formed from arachidonic acid (F2-isoprostanes) in healthy humans, as well as in those under oxidative stress. a-Linolenic acid (ALA) is a precursor to EPA and DHA; however, its conversion in humans is thought to be inefficient. ALA can also undergo free radical oxidation, forming compounds known as F1-phytoprostanes, which are found in all plants and are in high concentrations in plant pollens. In this study, we examined the effect of ALA supplementation on plasma and urine F1-phytoprostane and F2 -isoprostane concentrations in men. Thirty-six non-smoking men, aged 20 to 65 y, were recruited from the general population and randomly allocated to consume 9 g/d of either flaxseed oil (62% ALA, 5.4 g/d) or olive oil (placebo) for 4 wk in a parallel design. At baseline and after 4 wk of supplementation, blood samples and a 24-h urine sample were collected for measurement of plasma and urinary F1-phytoprostanes and F2-isoprostanes and plasma fatty acids. Compared with the olive oil group, plasma phospholipid ALA was greater (P< 0.0001), as were F 1-phytoprostanes in plasma (P = 0.049) and urine (P = 0.06) in the flaxseed oil group after 4 wk supplementation. Flaxseed oil did not affect plasma or urinary F2-isoprostanes. The greater plasma F1-phytoprostane concentration in the flaxseed oil group most likely resulted from the increased plasma concentration of the ALA substrate and/or the F1-phytoprostane content of the flaxseed oil. Future studies are needed to determine the physiological importance of increased plasma and urine F 1-phytoprostanes and their relevance to heart disease prevention. (Author's abstract)
With regard to cardiovascular disease (CVD), the role of the plant-derived (n-3) fatty acid, alpha-linolenic acid (ALA) is not clear. Oxidative stress resulting in lipid peroxidation is an important contributor to the atherosclerosis process. Free radical attack on the n-6 fatty acid arachidonic acid (AA) results in the formation of a group of metabolites called F2-isoprostanes. The levels of hydroperoxyoctadecanoic acids and F2-isoprostanes have been shown to be elevated in animal models of oxidative stress, and in humans with conditions associated with increased oxidative stress. The F2-isoprostanes are considered to be reliable markers of in vivo lipid peroxidation. The effect of ALA on oxidative stress and specifically F 2-isoprostanes has not been assessed. Like the long-chain (n-3) fatty acids, ALA can undergo free radical oxidation to an analogous group of compounds known as F1-phytoprostanes. The purpose of this study was to evaluate the effect of supplementation with ALA on F2-isoprostanes and F1-phytoprostanes. Men were chosen for the study because of the gender differences in conversion of ALA to the long-chain (n-3) fatty acids, in particular EPA. This study showed that supplementation with 9 g/d of flaxseed oil for 4 wk lead to significant increases in oxidation products of ALA (F 1-phytoprostanes) in plasma compared with olive oil. The increase in plasma F-1 phytoprostanes appeared to be due to an increase in ALA and/or intake of F1-phytoprostanes present in the flaxseed oil. Flaxseed oil did not affect oxidation products of AA (F 2-isoprostanes) in plasma or urine, indicating that flaxseed oil supplementation had no effect on plasma or whole-body lipid peroxidation. When the data was adjusted for changes in plasma ALA composition, the difference in plasma F 1-phytoprostanes between the 2 groups was no longer significant. Urinary excretion of F1phytoprostanes also tended to be elevated after flaxseed oil supplementation. Further research into the biological actions of F1 phytoprostanes is needed.  It is possible that ALA-induced F1-phytoprostane formation could beneficially affect inflammatory pathways and contribute to the reduced risk for myocardial infarction associated with ALA intake. In conclusion, supplementation of the diet of healthy men with flaxseed oil led to significant increases in the oxidation products of ALA known as F 1-phytoprostanes without affecting the F 2-isoprostanes derived from AA. This suggests that supplementation with large doses of flaxseed oil, similar to those used in this study, are unlikely to produce beneficial effects on oxidative stress in a manner similar to those for fish oils  Studies are required to determine the doses of ALA that increase F1-phytoprostane concentration. (Editor's comments)