Modification of dimethylhydrazine-induced carcinogenesis in rats by dietary cholesterol

Diets capable of affecting serum cholesterol levels were examined for effects on tumorigenesis in male Fischer 344 rats given 1,2-dimethylhydrazine dihydrochloride (DMH). Four regimens were used: Group A was maintained on a semipurified diet; Group B was maintained on the same diet with cholesterol and bile salts added; Group C was fed the cholesterol and bile salt diet and then switched to the semipurified diet; and Group D was fed the cholesterol and bile salt diet and then placed on a semipurified diet containing bile salts. Six months after DMH administration, Group B and D exhibited similar tumor incidence (77% and 83%, respectively) and yield (2.3 and 2.4 tumors/tumor-bearing rat). These yields were significantly greater than those seen in Group A (70% incidence and 1.4 tumors/tumor-bearing rat) or Group C (52% incidence and 1.7 tumors/tumor-bearing rat). Tumors in Groups B and D were larger in size and closer to the rectum than those seen in the other groups. In each of Groups A, C, and D, approximately 26% of the tumors were malignant; in Group B, 42% were malignant. Colonic epithelial cell kinetics in rats from Groups C and D not given DMH were determined using autoradiographic study of [3H]thymidine incorporation. Group D showed enhanced cell proliferation and expansion of the crypt cell population. These results suggest that dietary bile salts increase cell turnover and frequency of tumors, and that the addition of cholesterol to a cocarcinogenic diet can be associated with a significantly higher percentage of invasive tumors.