EXON-SPECIFIC DNA HYPOMETHYLATION OF THE P53 GENE OF RAT COLON INDUCED BY DIMETHYL HYDRAZINE - MODULATION BY DIETARY-FOLATE

Folate deficiency enhances colorectal carcinogenesis in dimethylhydraz ine-treated rats. Folate is an important mediator of DNA methylation, an epigenetic modification of DNA that is known to be dysregulated in the early stages of colorectal cancer, This study investigated the eff ect of dimethylhydrazine on DNA methylation of the colonic p53 gene an d the modulation of this effect by dietary folate, Sprague-Dawley rats were fed diets containing 0, 2, 8, or 40 mg of folate/kg of diet, Fiv e weeks after diet initiation, dimethylhydrazine was injected weekly f or fifteen weeks. Folate-depleted and folate-replete control animals d id not receive dimethylhydrazine and were fed the 0- and 8 mg folate d iets, respectively, The extent of p53 methylation was determined by a quantitative HpaII-polymerase chain reaction, In exons 6 and 7, signif icant p53 hypomethylation was observed in all dimethylhydrazine-treate d rats relative to controls (P < 0.01), independent of dietary folate, In exon 8, significant p53 hypomethylation was observed only in the d imethylhydrazine-treated folate-depleted rats compared with controls ( P = 0.038) and was effectively overcome by increasing levels of dietar y folate (P = 0.008). In this model, dimethylhydrazine induces exon-sp ecific p53 hypomethylation, In some exons, this occurs independent of dietary folate, and in others, increasing levels of dietary folate eff ectively override the induction of hypomethylation in a dose-responsiv e manner. This may be a mechanism by which increasing levels of dietar y folate inhibit colorectal carcinogenesis.