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Alteration of Methylation Patterns in Rat Liver Histones following Administration of Ethionine, a Liver Carcinogen¹

Cancer Research Laboratory, Veterans Administration Medical Center [R. C.], and Department of Biochemistry, University of Tennessee Center for the Health Sciences [R. C., M. T. T.], Memphis, Tennessee 38104

The possible role of alterations of histone methylation by ethionine in the mechanism of ethionine carcinogenesis was studied. In regenerating rat liver, histone synthesis was inhibited by only 20 to 30% with large doses of ethionine (0.75 to 1.0 mg/g body weight). The effect of ethionine on the in vivo methylation of histones was studied by giving 0.5 mg ethionine and [methyl-³H]methionine per g body weight. In vivo methylation of lysine was inhibited by 50%, whereas the arginine methylation was inhibited by 89%. The cellular localization of the methyltransferases and S-adenosyl-L-ethionine may be related to this differential effect. Utilizing an in vitro assay for protein-lysine and protein-arginine methyltransferases, we have demonstrated that the methyl-deficient histones are transported to the nucleus and with time lose their ability to accept methyl groups in vitro.

¹ This investigation was supported by the United States Veterans Administration (4323-01) and the American Cancer Society Institutional Research Grant 1N-85-N-4, University of Tennessee.

Received 3/17/80. Accepted 12/29/80.