Modulating Effect of Amount and Types of Dietary Fat on Colonic Mucosal Phospholipase A₂, Phosphatidylinositol-specific Phospholipase C Activities, and Cyclooxygenase Metabolite Formation during Different Stages of Colon Tumor Promotion in Male F344 Rats

Abstract

Epidemiological and laboratory animal model studies suggest that the effect of dietary fat in colon carcinogenesis depends not only on the amount but on its fatty acid composition. Animal model studies demonstrated that high dietary corn oil or safflower oil rich in omega-6 fatty acids increased the colon tumor promotion, whereas diets containing fish oil high in omega-3 fatty acids had no such enhancing effect. One of the mechanisms by which high dietary fat enhances colon carcinogenesis may be through the modulation of colonic mucosal phospholipase A₂ (PLA₂) and phosphatidylinositol-specific phospholipase C (PI-PLC), which are dominant pathways for arachidonic acid release and formation of eicosanoids. PI-PLC is also responsible for diacylglycerol formation and protein kinase C-dependent signal transduction and cell proliferation. In the present study, we investigated the modulating effect of high fat diets rich in omega-3 and omega-6 fatty acids on colonic mucosal PLA₂, PI-PLC activities, and eicosanoid (prostaglandins and thromboxane B₂) formation from arachidonic acid via cyclooxygenase (COX) during different stages of azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. At 5 weeks of age, groups of animals were fed the low-fat diet containing 5% corn oil. Beginning at 7 weeks of age, all animals except those intended for vehicle treatment received AOM s.c. once weekly for 2 weeks at a dose rate of 15 mg/kg body weight. Vehicle-treated groups received an equal volume of normal saline. One day after the second AOM or vehicle treatment, groups of animals were transferred to experimental diets containing 23.5% corn oil and 20.5% fish oil + 3% corn oil, whereas one group continued on the low-fat diet containing 5% corn oil. Groups of animals were then sacrificed at weeks 1, 12, and 36 after the second AOM-or saline-treatment. Colonic mucosa harvested at weeks 1, 12, and 36 and colonic tumors obtained at week 36 were analyzed for PLA₂, PI-PLC, and eicosanoid formation from arachidonic acid by the action of COX. The results demonstrate that colon carcinogen treatment increases the activities of colonic mucosal PLA₂ and PI-PLC and the formation of prostaglandins and thromboxane A₂ from arachidonic acid through COX throughout the study period compared to saline-treated animals fed similar diets. The activities of PLA₂, PI-PLC, and COX were significantly higher in colon tumors compared to colonic mucosa. These results also demonstrate that a high-fat diet containing corn oil increases colonic mucosal and tumor PLA₂ and PI-PLC and the formation of prostaglandins and thromboxane B₂ by the action of COX as compared to low dietary corn oil or a diet high in fish oil. The results of our study offer one of the mechanisms by which the amount and types of dietary fat modulate colon carcinogenesis.