Dietary inadequacy of
folate enhances and
folate supplementation suppresses colorectal
carcinogenesis in the
dimethylhydrazine rat model.
Folate is an essential factor for DNA methylation and the de novo biosynthesis of
nucleotides, aberrations of which play important roles in mutagenesis. This study investigated whether the mutational hot spots of the Apc and p53 genes for human
colorectal cancer are mutated in
dimethylhydrazine-induced
colorectal neoplasms and whether dietary
folate can modulate mutations in these regions. Rats were fed diets containing 0, 2 (basal requirement), 8 or 40 mg
folate/kg diet. Five weeks after diet initiation,
dimethylhydrazine was injected weekly for 15 weeks. Mutations were determined by direct sequencing in 11 low and seven high grade dysplasias and 13 invasive
adenocarcinomas. A total of six Apc mutations were found in four dysplastic and carcinomatous lesions: two in two low grade dysplasias, two in one high grade dysplasia and two in one
adenocarcinoma. All mutations were single base substitutions, four of which were A:T-->G:C transitions. Five of the six mutations were located upstream from the region corresponding to the human APC mutation cluster region. Dietary
folate had no effect on the frequency and type of Apc mutations. No mutations were detected in exons 5-9 of the p53 gene in neoplastic lesions. These data suggest that in the
dimethylhydrazine rat model of
colorectal cancer, the Apc gene is mutated in early stages, albeit to a lesser degree than observed in human
colorectal cancer, whereas the mutational hot spot of the p53 gene for human
colorectal cancer is not commonly mutated. Although the low frequency of Apc mutations and the small number of
neoplasms studied in this study might have precluded our ability to observe modulatory effects of
folate, dietary
folate appears to have no significant effect on Apc and p53 mutations.