Enhancement of colon and stomach carcinogenesis in 1,2-dimethylhydrazine-treated rats fed a diet high in heterocyclic amines

Abstract

Epidemiological studies have linked the consumption of red meat and the consumption of highly browned meats containing high levels of heterocyclic aromatic amines (HCAs) to increased risk of colorectal cancer or polyps. We have examined the effects of long-term feeding of beef-containing diets with low and high levels of HCAs (in the context of a low- or high-beef tallow diet) on a standard 1,2-dimethylhydrazine (DMH)-induced colon tumorigenesis protocol. Feeding of a beef diet high in HCAs resulted in more DMH-induced colon adenocarcinomas, but only in the context of a low fat diet. The high HCA diets increased stomach tumors in all DMH-treated rats. An apparent interaction of high HCA levels with a high fat level reduced the colon tumor incidence and tumor numbers in those rats on diets containing both these factors. These results support the epidemiological data linking well-cooked meat to increased risk for colon and stomach cancer, but the role of the dietary fat level remains puzzling. Additionally, we examined the DNA of liver, colon, and stomach from control rats (not treated with DMH) fed a high level of HCAs for 27 weeks. The genomic DNA was analyzed for the presence of 2-amino-1-methyl-6-phenylimidazo[4,5-f]pyridine (PhIP) adducts by 32P-postlabeling analysis and was also used in PCR to amplify the rat p53 and Apc genes, followed by direct dye-terminator DNA sequencing. Results showed that no PhIP adducts were present in any tissue. In addition, there were no signature p53 or Apc gene mutations seen in the colon or stomach DNA. These results indicate that the high level of HCAs present in a diet of well-cooked meat does not cause (1) persistent PhIP adducts similar to those produced by feeding pure PhIP at high doses or (2) p53 and Apc gene mutations in nontumor tissue.