Effect of Cholic Acid Feeding on N-Methyl-N-nitrosourea-Induced Colon Tumors and Cell Kinetics in Rats 23

Abstract

The tumor-inducing effects of cholic acid feeding were examined in cesarean-derived F344 rats treated with intrarectally administered N-methyl-N-nitrosourea (MNU). The rats were divided into 4 treatment groups. Group 1 received control chow; group 2, control chow and cholic acid (0.2%); group 3, control chow and 8 mg MNU; and group 4, control chow plus 0.2% cholic acid and 8 mg MNU. At 28 weeks, rats in groups 1 and 2 had no tumors. Group 3 had a tumor incidence of 54% (1.1 tumors/animal), whereas rats in group 4 had a tumor incidence of 62% (1.8 tumors/animal). Significantly more tumors were seen in group 4 than in group 3 (modified chi-square, P<0.05). Tumors were primarily adenomas, but invasive adenocarcinomas were also detected. The tumors increased in size from adenomas to invasive carcinomas. Analyses at week 28 revealed a slight increase in fecal neutral sterols in groups 3 and 4 compared with their respective controls (2.17 vs. 1.90 and 2.22 vs. 1.65 mg/g). Conversion of cholesterol to coprostanol was similar in all groups (averaging 65% in groups 1 and 3 and 64% in groups 2 and 4). Total fecal bile acid output was elevated in the cholic acid-fed rats compared with their controls (9.52 vs. 3.68 mg/g feces). The major fecal bile acid in groups 2 and 4 was deoxycholic acid, whereas the amounts of cholic acid were similar in all groups. Deoxycholic acid was presumed to be the primary tumor promoter (or cocarcinogen). Cell kinetics were measured at weeks 5 and 19. At 5 weeks groups 2 and 4 showed enhanced cell proliferation over control values. Cell proliferation was also increased as a result of the MNU-induced damage (group 3). The cumulative effect of MNU and cholic acid feeding increased the numbers of epithelial cells that underwent DNA synthesis. The heightened cell turnover allowed tumors to occur with greater frequency as seen in the cholic acid- plus MNU-treated rats.