Carcinogenesis and DNA Hypomethylation in Methyl-Deficient Animals
The current increasing interest in the possible role of normal DNA methylation in carcinogenesis has sprung from three major sources: (1) cell culture studies on the role of DNA methylation in cell differentiation; (2) hypomethylation of specific genes in a variety of cancers; and (3) liver cancer causation in methyl-deficient rats. Studies on the role of DNA methylation in mammalian cell differentiation conducted by Christman et al., 1977, and Razin and Riggs, 1980, led to the postulate that undermethylation of the C5 position of cytosine may play a determining role in cancer causation (Holliday, 1979; Riggs and Jones, 1983). Feinberg and Vogelstein (1983b) showed that the genes coding for human growth hormone, α-globin, and γ-globin in human tumors were undermethylated compared to the same genes in the corresponding normal tissues. Subsequent studies have extended these observations to include other tumors and genes (Hoffman, 1984). Finally, dietary deprivation of the methyl donors methionine and choline had been shown to induce liver carcinomas in rats (Copeland and Salmon, 1946). Although these findings were accepted for a period of nearly 10 years, the subsequent demonstration of aflatoxin contamination in the peanut meal-based diets used to produce the methionine- and choline-deficiency, led credence in these findings to be suspended (Newberne, 1965). However, a second system to produce liver tumors in association with a methyl-deficient state was seen by the chronic administration of ethionine to rats (Farber, 1963).
KeywordsFolic Acid Methionine Choline Homocysteine Chol
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