Neoplastic conversion of rat liver epithelial cells in culture by ethionine and S-adenosylethionine

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Abstract
Rat liver epithelial cells were grown in the presence of the hepatocarcinogen, DL-ethionine, for 12 weeks. The cells were then cultured for an additional 32 weeks in carcinogen-free medium. At approximately monthly intervals, the cells were tested for transformation by assaying their ability to grow in soft agar and to produce tumors when injected s.c. into irradiated syngeneic rats. After a total of 34 weeks in culture, cells treated with 7.5 mM DL-ethionine were transformed according to both criteria. The experiment was repeated using medium in which methionine was replaced by its metabolic precursor, homocysteine. The cells were treated for 12 weeks with L-ethionine and its metabolite, S-adenosyl-L-ethionine (L-AdoEt), then cultured in their absence in methionine-containing medium for an additional 24 weeks. After a total of 20 weeks in culture, cells treated with 0.375 mM L-ethionine and cells treated with 0.2 mM L-AdoEt produced tumors following their injection into animals. Positive growth in soft agar was observed 5 and 11 weeks later, respectively. A total of 31 weeks in culture was required before cells treated with 0.2 mM L-ethionine became tumorigenic. Furthermore, tumors resulting from the injection into animals of cells treated with 0.2 mM L-ethionine arose 8–10 weeks later than did the corresponding tumors arising from the cells treated with 0.2 mM L-AdoEt. Thus, the results indicate that AdoEt may be a proximal carcinogenic metabolite of ethionine.