It is evident from many studies that the effect of dietary fat on colon tumor promotion depends not only on the amount of fat but especially on fatty acid composition. Animal model studies have shown that diets which are high in omega-6 fatty acids increase colon tumor promotion, whereas diets rich in omega-3 fatty acids have no such enhancing effect. The mechanisms by which the high fat content of the diet promotes colon carcinogenesis may include the production of secondary bile acids in the colon and the modulation of colonic luminal bacterial 7α-dehydroxylase that is involved in generating secondary bile acids, phosphatidylinositolspecific phospholipase C (PI-PLC), and mucosal PI-PLC, as well as diacylglycerol (DAG) kinase and protein kinase C (PKC). In the present study, we investigated the effect of high-fat diets that are rich in omega-3 and omega-6 fatty acids on cecal bacterial 7α-dehydroxylase and PI-PLC, fecal secondary bile acids, and colonic mucosal DAG kinase and PKC activities during different stages of colon carcinogenesis in male F344 rats. At 5 weeks of age, groups of animals were fed a low-fat diet containing 5% corn oil (LFCO). Beginning at 7 weeks of age, all animals, except those intended as vehicle controls, received azoxymethane (AOM) s.c. once weekly for 2 weeks at a dose rate of 15 mg/kg body weight. Vehicle-treated groups received s.c. injections of normal saline. One day after the second AOM or saline treatment, the experimental groups of animals were transferred to a high-fat diet containing 23.5% corn oil (HFCO) or 20.5% fish oil + 3% corn oil (HFFO). One group continued on the LFCO diet. Animals were sacrificed at weeks 1, 12, and 36 after the AOM or saline treatment. Colonic mucosa were harvested at weeks 1, 12, or 36, and the colonic tumor tissues were examined for PKC and DAG kinase activities. Contents of the cecum were analyzed for bacterial 7α-dehydroxylase and PI-PLC activities. Stool samples collected at week 12 were analyzed for bile acids.

High corn oil content of the diet significantly increased the cecal bacterial 7α-dehydroxylase and PI-PLC activities as compared to the diets with high fish oil or low corn oil content. Animals fed the HFCO diet excreted higher levels of secondary bile acids, such as deoxycholic acid and lithocholic acid, than those fed the LFCO or HFFO diets. Carcinogen treatment significantly enhanced the activities of DAG kinase and total membrane PKC activities in colonic mucosa compared to saline treatment in all dietary groups. Animals treated with saline or AOM and fed HFCO showed increased levels of DAG kinase and membrane PKC activities in the colonic mucosa when compared to LFCO and HFFO groups. DAG kinase and membrane PKC activities were higher in colon tumors than in the surrounding colonic mucosa, and also increased levels of these enzyme activities were found in the HFCO diet group. These results indicate that the modifying effect of dietary fat on colonic bacterial enzymes, secondary bile acids, colonic mucosal and tumor DAG kinase, and PKC that may play a role in colon carcinogenesis depends on the types and amount of fat given. The colon tumor-enhancing effect of a HFCO diet in contrast to the high dietary fish oil may be, in part, explained on the basis of its modulating effect on these bacterial and colonic mucosal enzymes and colonic secondary bile acids relevant to colon tumor promotion.


Supported by USPHS Grants CA-17613 and CA-37663, awarded by the United States National Cancer Institute.

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