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Interaction between Ethionine and Rat Liver Ribonucleic Acid and Protein In Vivo¹

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and Toxicology Research Unit, Medical Research Council Laboratories, Carshalton, Surrey, England [P.N.M.]

The interactions of ethionine and methionine with RNA and protein fractions in acute experiments and under conditions leading to liver cancer have been studied. Following the injection of L-ethionine-ethyl-l-¹⁴C into rats, radioactivity was regularly found in RNA and protein of liver, pancreas, kidney, and spleen, but the highest by far was in liver RNA and pancreatic protein. The pattern of labeling was different than that following the injection of methionine-methyl-¹⁴C, glycine, serine, acetate (C₁ and C₂), or ethanol (C₁ and C₂). The labeling pattern of the total liver RNA and protein was similar with L-ethionine-ethyl-1-¹⁴C and L-ethionine-ethyl-1-³H and different with L-ethionine-³⁵S. The most radioactive fractions of the liver following 7 daily injections of radioactive ethionine were soluble RNA and nuclear protein. Of the nuclear protein fractions studied, the highest specific activity was found in a fraction soluble in 0.14 M NaCl. In contrast to ethionine, the injection of ¹⁴CCl₄ labeled total liver RNA to an insignificant degree and liver protein to a small degree. Acid hydrolysis of liver RNA labeled with L-ethionine-ethyl-1-¹⁴C followed by chromatography on Dowex 50 revealed at least 4 peaks of radioactivity, only 1 of which coincided with a peak of ultraviolet absorption, uridylic acid. By means of paper chromatography and paper electrophoresis, it was possible to separate all the radioactive components from ultraviolet-absorbing compounds. The labeling of RNA and protein fractions with radioactive ethionine or methionine were compared in animals fed control diets or diets containing ethionine, ethionine-methionine, or methionine for periods of 1, 2, 3, or 4 months. The patterns were generally similar at each of these time periods. The labeling of animals on the ethionine-methionine diet was, in most instances, less than in animals on the ethionine diet, but a considerable degree of labeling always occurred in the former group, even though they did not develop liver cancer. The possible relationship of the labeling of RNA and protein to liver carcinogenesis is discussed.

¹ This research was supported in part by the American Cancer Society, the Beaver County Cancer Society, and the USPHS Research Grants CA-06074 from the National Cancer Institute, GM-10209, and GM-2G-135 (a raining grant) from the National Institute for General Medical Sciences.

² Part of this research was done in Carshalton, England, during 1960, while this author was an American Cancer Society Research Professor of Pathology and Biochemistry at Tulane University School of Medicine, New Orleans, Louisiana. A preliminary report of some of this work has been published (20).

³ Sarah Mellon Scaife Fellow in Pathology, 1961–1963.

⁴ Recipient of a Special Fellowship from the National Institute of Neurological Diseases and Blindness, NIH, USPHS.

Received 1/25/66. Accepted 5/23/67.