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Composition, Associated Tissue Methyltransferase Activity, and Catabolic End Products of Transfer RNA from Carcinogen-induced Hepatoma and Normal Monkey Livers

Laboratory of Chemical Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland 20014 [D. B. L., T. P. W., J. L., R. H. A.]; Department of Biochemistry and Experiment Station Chemical Laboratories, University of Missouri, Columbia, Missouri 65201 [C. W. G.]; Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830 [J. E. M.]; and Department of Microbiology, University of Colorado Medical Center, Denver, Colorado 80220 [E. B.]

This investigation was designed to explore transfer RNA tRNA) methyltransferase activity, urinary excretion levels of RNA degradation products, and tRNA base composition in normal monkeys and in those with hepatocellular carcinonas induced by N-nitrosodiethylamine. After the development of the tumor, 24-hr urine specimens were collected, the monkeys were sacrificed, and the livers were removed or tRNA isolation and methyltransferase activity studies. The tRNA methyltransferase activity and capacity and the urinary excretion levels for selected tRNA degradation products (pseudouridine, N²,N²-dimethylguanosine, 1-methylinosine, 7-methylguanine, and ß-aminoisobutyric acid) were elevated for the hepatoma-bearing monkeys when compared to those with normal liver. The isolated RNA pools were analyzed by high-resolution liquid chronatography, and similar base compositions were found for the hepatoma-bearing and normal monkeys. With the use of methyl-deficient Escherichia coli tRNA as the methyl receptor or and the analytical procedure for tRNA analysis, the methylating ability of the tRNA methyltransferases in hepatoma and normal liver extracts was determined. The hepatoma methyltransferase homogenates were found to produce increased levels of 7-methylguanine, N²,N²-dimethylguanine, and thymine, while the normal liver extracts gave higher levels of N²-methylguanine. These differences were not apparent in the base composition of the tRNA pools. The increased urinary excretion and higher methyltransferase activity of the hepatoma-bearing monkeys without an apparent increase in the methylated base content of their tRNA suggest increased tRNA turnover. However, subtle changes in the methylated base content of individual isoaccepting tRNA's would be missed by analyzing the tRNA pools. The variations in the individual tRNA methyltransferase activities of the hepatoma and normal liver homogenates indicate a difference in the methylation of their tRNA's.

¹ To whom requests for reprints should be addressed, at Laboratory of Chemical Pharmacology, Building 37, Room 5A15, National Cancer Institute, NIH, Bethesda, Md. 20014.

Received 7/14/76. Accepted 10/18/76.