Introduction: Prostaglandin (PG) E2 has been linked to higher risk of colorectal carcinogenesis. Our previous in vitro data (Wada et al. J Biol Chem 2007;282;22254) demonstrated reduction of cellular eicosanoids by substituting the n-3 fatty acid EPA for the more common n-6 FA arachidonic acid (AA) as substrate for the cyclooxygenases (Cox). We tested the hypothesis that EPA substitution for n-6 FA in vivo will reduce procarcinogenic eicosanoids in rats.

Methods: F344 male rats were fed EPA: n-6 FA ratio diets of 0, 0.1, 0.2, 0.4, 0.6 for 5 weeks. Eicosanoids (PGs and lipoxins) in proximal, transverse and distal colonic tissue and urinary PG metabolites were assayed on LC-MS-MS. Fatty acids in serum and tissue were measured by GC-MS.

Results: Serum EPA:AA ratio (means(SD)) increased linearly from 0.02(0.004) at baseline (no EPA) to 0.98(0.32) EPA:n-6 ratio of 0.6. Colonic EPA:AA ratios increased from 0.03(0.01) to 0.41(0.15) in distal colon. Representative eicosanoid concentrations (μg/mg protein) in distal colon tissue with associated EPA:n-6 diets in the Table suggest rapid eicosanoid reduction at lower dietary EPA:n-6 ratios and then flattening of the dose response at higher ratios. The distal colon contained the lowest eicosanoid concentrations compared to transverse and proximal colon. Urinary PGE metabolite was reduced from 13.42(1.95) ng/mg creatinine (dietary EPA:n-6 FA=0) to 7.67(0.62) ng/mg creatinine (dietary EPA:n-6 FA=0.6).

Conclusion: Diet induced substitution of omega-3 for omega-6 substrates of Cox and lipoxygenases in F-344 rats causes a rapid, non-linear decline in colonic PGE2 and lipoxin products. PGE3 increases linearly with omega-3 FA dose. These data support the hypothesis that reduction in carcinogenesis stress induced by eicosanoids can be modulated by a dietary intervention in vivo.

Eicosanoids in rat colon

EPA: n-6 ratio in dietPGE2PGE35-HETE12-HETE
264.43(77.54) 0.12 (0.14) 2.28 (1.74) 35.67 (26.95) 
0.2 116.56 (50.53) 0.89 (0.81) 1.15 (0.99) 11.73 (7.65) 
0.4 86.15 (27.28) 1.52 (0.96) 1.80 (2.02) 5.93 (4.01) 
0.6 90.89 (20.90) 2.17 (1.36) 1.52 (0.78) 5.68 (2.77) 
EPA: n-6 ratio in dietPGE2PGE35-HETE12-HETE
264.43(77.54) 0.12 (0.14) 2.28 (1.74) 35.67 (26.95) 
0.2 116.56 (50.53) 0.89 (0.81) 1.15 (0.99) 11.73 (7.65) 
0.4 86.15 (27.28) 1.52 (0.96) 1.80 (2.02) 5.93 (4.01) 
0.6 90.89 (20.90) 2.17 (1.36) 1.52 (0.78) 5.68 (2.77) 

Citation Format: Yan Jiang, Zora Djuric, Jianwei Ren, Kuklev V. Dmitry, Austin Curtis, Gretchen S. Bentz, Ian Waters, Ananda Sen, Lili Zhao, Charis Uhlson, Robert Murphy, William L. Smith, Dean E. Brenner. Prostaglandin and associated eicosanoid dose response to omega-3 fatty acid (FA) diet in rat colon. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4863. doi:10.1158/1538-7445.AM2013-4863