Plasma oxylipins respond in a linear dose-response manner with increased intake of EPA and DHA: results from a randomized controlled trial in healthy humans

Am J Clin Nutr. 2019 May 1;109(5):1251-1263. doi: 10.1093/ajcn/nqz016.


Background: The health effects of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) are partly mediated by their oxidized metabolites, i.e., eicosanoids and other oxylipins. Some intervention studies have demonstrated that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increase systemic concentrations of n-3 PUFA-derived oxylipins and moderately decrease arachidonic acid-derived oxylipins. There is no information on the dose-response of oxylipin concentrations after n-3 PUFA intake.

Objective: The aim of this study was to quantify oxylipins in human plasma samples from an intervention study in which participants were randomly assigned to different daily intakes of EPA and DHA for 12 mo.

Methods: Healthy adult men and women with low habitual fish consumption (n = 121) were randomly assigned to receive capsules providing doses of n-3 PUFAs reflecting 3 patterns of consumption of oily fish [1, 2, or 4 portions/wk with 3.27 g EPA + DHA (1:1.2, wt:wt) per portion] or placebo. Oxylipins were quantified in plasma after 3 and 12 mo. Relative and absolute changes of individual oxylipins were calculated and concentrations were correlated with the dose and the content of EPA and DHA in blood lipid pools.

Results: Seventy-three oxylipins, mostly hydroxy-, dihydroxy-, and epoxy-PUFAs, were quantified in the plasma samples. After 3 and 12 mo a linear increase with dose was observed for all EPA- and DHA-derived oxylipins. Cytochrome-P450-derived anti-inflammatory and cardioprotective epoxy-PUFAs increased linearly with n-3 PUFA dose and showed low interindividual variance (r2 > 0.95). Similarly, 5, 12-, and 15-lipoxygenase-derived hydroxy-PUFAs as well as those formed autoxidatively increased linearly. These include the precursors of so-called specialized pro-resolving lipid mediators (SPMs), e.g., 17-hydroxy-DHA and 18-hydroxy-EPA.

Conclusions: Plasma concentrations of biologically active oxylipins derived from n-3 PUFAs, including epoxy-PUFAs and SPM-precursors, increase linearly with elevated intake of EPA and DHA. Interindividual differences in resulting plasma concentrations are low. This trial was registered at as ISRCTN48398526.

Keywords: DHA; EPA; dose-response; eicosanoids; essential fatty acids; fish oil; inflammation; omega-3 polyunsaturated fatty acids; oxylipins; ratio of n–3 to n–6 fatty acids.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Diet*
  • Docosahexaenoic Acids / administration & dosage
  • Docosahexaenoic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Eicosapentaenoic Acid / administration & dosage
  • Eicosapentaenoic Acid / pharmacology*
  • Feeding Behavior*
  • Female
  • Fishes
  • Humans
  • Lipids / blood
  • Male
  • Middle Aged
  • Oxylipins / blood*
  • Seafood
  • Young Adult


  • Lipids
  • Oxylipins
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid