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

• Published in: The Journal of nutritional biochemistry 2012-08, Vol.23 (8), p.966-976
• Main Authors: Neilson, Andrew P, Djuric, Zora, Ren, Jianwei, Hong, Yu H, Sen, Ananda, Lager, Corey, Jiang, Yan, Reuven, Shony, Smith, William L, Brenner, Dean E
• Format: Article
• Language: English
• Subjects: Animals; arachidonic acid; Biological and medical sciences; Cell Proliferation; colon; Colon - metabolism; Colon cancer; colorectal neoplasms; Cyclooxygenase; Cyclooxygenase 1 - genetics; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; diet; Dietary Fats, Unsaturated - administration & dosage; Dietary Fats, Unsaturated - pharmacology; Eicosanoids - metabolism; eicosapentaenoic acid; EPA; Feeding. Feeding behavior; Female; Fish oil; fish oils; Fish Oils - administration & dosage; Fish Oils - pharmacology; Fundamental and applied biological sciences. Psychology; Genotype; Hydroxyeicosatetraenoic acids; Hydroxyeicosatetraenoic Acids - metabolism; immunohistochemistry; liquid chromatography; mass spectrometry; Membrane Proteins - genetics; Membrane Proteins - metabolism; menhaden; metabolites; Mice; Mice, Inbred Strains; mucosa; nonsteroidal anti-inflammatory agents; oleic acid; olive oil; Prostaglandin E2; prostaglandin synthase; prostaglandins; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2011.05.003

Dietary ω3 fatty acids can modulate substrate availability for cyclooxygenases (COXs) and lipoxygenases, thus modulating downstream eicosanoid formation. This could be an alternative approach to using nonsteroidal anti-inflammatory drugs and other COX inhibitors for limiting Prostaglandin E2 (PGE2) synthesis in colon cancer prevention. The aims of this study were to evaluate to what extent COX- 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 the 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 weeks. Colonic eicosanoid levels were measured by liquid chromatography tandem mass spectroscopy (LC-MS/MS), and proliferation was assessed by Ki67 immunohistochemistry. For the dietary alteration of colonic arachidonic acid: eicosapentaenoic ratios resulted in large shifts in formation of COX and lipoxygenase metabolites. COX-1 knockout virtually abolished PGE2 formation, but interestingly, 12-hydroxyeicosatetraenoic (12-HETE) acid 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.