Effect of cyclooxygenase genotype and dietary fish oil on colonic eicosanoids in mice

Abstract

Dietary ω3 fatty acids can modulate substrate availability for cyclooxygenases and lipoxygenases, thus modulating downstream eicosanoid formation. This could be an alternative approach to using NSAIDs and other COX inhibitors for limiting PGE2 synthesis in colon cancer prevention. The aims of this study were to evaluate to what extent cyclooxygenase- and lipoxygenase-derived products could be modulated by dietary fish oil in normal colonic mucosa, and to evaluate the role of COX-1 and COX-2 in formation of these products. Mice (wild-type, COX-1 null, or COX-2 null) were fed a diet supplying a broad mixture of fatty acids present in European/American diets, supplemented with either olive oil (oleate control diet) or menhaden (fish) oil ad libitum for 9–11 wk. Colonic eicosanoid levels were measured by LC-MS/MS, and proliferation was assessed by Ki67 immunohistochemistry. Dietary alteration of colonic arachidonic acid: eicosapentaenoic ratios resulted in large shifts in formation of cyclooxygenase and lipoxygenase metabolites. COX-1 knockout virtually abolished PGE2 formation but interestingly 12-HETE and 15-HETE formation was increased. The large changes in eicosanoid profiles were accompanied by relatively small changes in colonic crypt proliferation, but such changes in eicosanoid formation might have greater biological impact upon carcinogen challenge. These results indicate that in normal colon, inhibition of COX-2 would have little effect on reducing PGE2 levels.

Healthy effect of different proportions of marine ω-3 PUFAs EPA and DHA supplementation in Wistar rats: Lipidomic biomarkers of oxidative stress and inflammation

“…They found a decrease of ω-6/ω-3 ratio and ARA proinflammatory metabolites (i.e., LTB 4 , 15HETE, TXB 2 ) in a microenvironment of acute human wounds; meanwhile an increase of EPA anti-inflammatory derivates (i.e., 5-12-15HEPE, PGD 3 , PGE 3 , TXB 3 ) and 18HEPE, precursor of anti-inflammatory RvE 1 [17]. Similar results have been achieved by Neilson et al in dietary experiments in rats [18].…”

“…In detail, ARA ω-6 eicosanoids like PGE 2 and 11HETE, have been widely studied and identified as a key pro-inflammatory signaling molecules related with pro-aggregating, vasoconstrictive and immunosuppressive processes [9]; and they have also been associated with promotion of different human cancers including colon, lung, breast, head or neck [3]. On the other hand, derived eicosanoid and docosanoids from EPA and DHA have been related with protective effects on inflammation diseases [16], the regulation of tumor factors [18], or the reduction of CVD risk [10]. However, hydroxides and hydroperoxides derived from EPA and DHA were also considered as biomarkers of oxidative stress and weaker inflammatory substances than the corresponding ARA derivates [2,31].…”

Effects of a Mediterranean Diet Intervention on Anti- and Pro-Inflammatory Eicosanoids, Epithelial Proliferation, and Nuclear Morphology in Biopsies of Normal Colon Tissue

“…Phytochemicals from plant based foods and olive oil both have been shown to decrease the activity of COX and LOX [25]. High amounts of dietary n-3 fatty acids decreased PGE 2 concentrations in the mouse colon [21]. Oleic acid (n-9) from olive oil does not appear to be a substrate for COX, but it may have allosteric effects on inhibiting COX activity [26, 27].…”

“…Reverse-phase liquid chromatography with tandem mass spectral detection (LC-MS-MS) was used to profile eicosanoids (PGE 2 , PGE 3 , LTB 4 , LTB 5 , 5-HETE, 12-HETE, 15-HETE, 13-HODE) using methods previously developed for rodent tissues [21]. Briefly, homogenates of four frozen colon biopsies, each about 5 mg tissue, were prepared.…”

Reducing Proinflammatory States with the Mediterranean Diet

“…The eicosanoid produced from eicosapentanoic acid is PGE3, and the biological activity of PGE3 is currently being investigated. Similarly, when eicosapentanoic acid is present, 5-LOX forms leukotriene B5 rather than leukotriene B4 [38]. The biological actions of these eicosanoids derived from n-3 fatty acids is not well described as of yet, but it is presumably beneficial relative to the mediators produced from n-6 fatty acids.…”