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In the preceding paper (Magee & Hultin, 1962) it was shown that methylation of proteins of ratliver slices occurred during incubation of the slices with the hepatotoxin and carcinogen dimethylnitrosamine. This finding supports the hypothesis that dimethylnitrosamine undergoes enzymic oxidative N-demethylation in the liver with subsequent intracellular fornation of a methylating agent, possibly diazomethane. Evidence for reaction with nucleic acids was also obtained. The reactions of nucleic acids and their components with alkylating agents have been studied very extensively in vitro

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Fischer 344 male rats fed a choline-methionine deficient diet for from 13 to 24 months developed a 100% incidence of putative preneoplastic hepatocyte nodules and a 51% incidence of hepatocellular carcinoma. The addition of 0.8% choline chloride completely prevented the development of both the nodules and the cancer. The diet contained no added known carcinogen. Analysis of the deficient and supplemented diets revealed no detectable volatile nitrosamines or nitrosamides, nitrite, nitrate or malonaldehyde, less than 0.9 p.p.b. aflatoxin B1 and barely detectable levels of Ames positive material with one strain of Salmonella typhimurium. These findings indicate that a dietary deficiency of choline and methionine can be a major rate limiting factor in the development of liver cancer.