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
7 alpha-dehydroxylase that is involved in generating secondary
bile acids,
phosphatidylinositol-specific 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
7 alpha-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
7 alpha-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
7 alpha-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.