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Comparison of Some Carcinogenic, Mutagenic, and Biochemical Properties of S-Vinylhomocysteine and Ethionine¹

McArdie Laboratory for Cancer Research, University of Wisconsin Center for health Sciences, Madison, Wisconsin 53706

Some carcinogenic, mutagenic, and biochemical properties of DL-ethionine and S-vinyl-DL-homocysteine (vinthionine) were compared to examine a possible role of vinthionine as a proximate carcinogenic metabolite of ethionine. Both DL-amino acids induced hepatic carcinomas in essentially all of the male Fischer rats fed these structurally similar compounds for 16 to 20 months as 0.1% of a 16% casein, choline-supplemented diet; the tumors appeared sooner in the rats fed ethionine than in those fed vinthionine. Administration in a methyl-deficient diet facilitated DL-ethionine-induced carcinogenesis more than DL-vinthionine-induced carcinogenesis. Multiple i.p. injections over a 12-week period of DL-vinthionine (total dose, 7 mmol/kg body weight) induced hepatocellular carcinomas in 9 of 28 and 6 of 28 male Fischer rats, respectively, that were or were not subsequently treated with phenobarbital until the termination of the experiment at 25 months. DL-Ethionine had only marginal carcinogenic activity under these conditions. Approximately 50% of female CD-1 mice fed 0.1% of DL-vinthionine or DL-ethionine in the 16% casein, choline-supplemented diet developed hepatomas by 18 months; male CD-1 mice were less susceptible.

L- or DL-vinthionine, but not L-, D-, or DL-ethionine, was a strong direct mutagen for Salmonella typhimurium strain TA100. L-Vinthionine (16 revertants/nmol) was about 30% more mutagenic than the DL mixture was. DL-Vinthionine sulfoxide and N-acetyl-DL-vinthionine methyl ester were only weakly mutagenic. Of several compounds that interfere with the metabolism of ethionine or its carcinogenic activity, only L-methionine (1000 nmol/plate) completely protected strain TA100 against the mutagenic activity of L-vinthionine (60 nmol/plate).

Administration of a single i.p. dose of DL-vinthionine (1 g/kg body weight) to rats caused a reduction in the hepatic level of adenosine triphosphate, but DL-vinthionine was less effective than DL-ethionine. However, attempts to demonstrate the accumulation of S-adenosylvinthionine in the livers of vinthionine-treated rats or mice or as a product of L-vinthionine with an adenosine triphosphate-supplemented yeast extract capable of converting either DL-methionine or DL-ethionine to their S-adenosyl derivatives were unsuccessful.

After a single i.p. injection, ¹⁴C from L-[vinyl-¹⁴C]vinthionine was bound to rat liver DNA, RNA, and protein. The magnitude of the binding to DNA (110 pmol/mg DNA 18 hr after a single i.p. injection of 31 mg/kg body weight) was of the order of that observed for strong hepatic carcinogens and much greater than the very low levels reported for L-[ethyl-³H or ethyl-¹⁴C] ethionine.

¹ This work was supported by Grants CA-07175, CA-09135, and CA-22484 from the National Cancer Institute, USPHS.

² Present address: Warner-Lambert, 2800 Plymouth Road, Ann Arbor, Mich. 48105.

³ To whom requests for reprints should be addressed.

Received 4/26/82. Accepted 7/15/82.

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