Molecular Pharmacology, Vol 9, 297-303, Copyright © 1973 by the American Society for Pharmacology and Experimental Therapeutics

The Effect of 5-Fluorodeoxyuridine on the Synthesis of Deoxyribonucleic Acid Pyrimidines in Precancerous Rat Liver

¹ McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

Precancerous livers were induced in rats by feeding the animals a diet containing 0.05 % (w/w) of the hepatocarcinogenic azo dye-3'-methyl-4-dimethylaminoazobenzene for 3 weeks. The contribution of de novo gnd salvage pathways to the synthesis of DNA pyrimidines in precancerous liver in vivo was monitored by simultaneously measuring the incorporation of [6-¹⁴C]orotic acid into DNA cytosine and DNA thymine and of [methyl-³H]-thymidine into DNA thymine, respectively. The incorporation of these precursors into total liver DNA, the DNA of hepatic cell suspensions, and the DNA of different classes of hepatic nuclei was determined. In addition, the activities of deoxycytidine monophosphate deaminase (dCMP aminohydrolase, EC 3.5.4.12), thymidine kinase (ATP: thymidine 5'-phosphotransferase, EC 2.7.1.21) and thymidylate synthetase (EC 2.1.1b) were measured in hepatic cell suspensions and in whole homogenates prepared from precancerous liver. These studies emphasize that, with regard to several aspects of pyrimidine nucleotide metabolism, precancerous liver is composed of a heterogeneous population of cells. The use of thymidine incorporation as the sole measure of the rate of DNA synthesis is shown to be questionable, and it is suggested that simultaneous assessment of both de novo and salvage pathways for the synthesis of DNA precursors is required for an accurate estimate of the extent of DNA synthesis.

Note:
ACKNOWLEDGMENTS The authors wish to thank Drs. J. A. and E. C. Miller for providing the special diets used in these studies, and Dr. C. Heidelberger for providing the FUdR.

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