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Inhibition of Rat Dihydropyrimidine Dehydrogenase by 5-Cyanouracil in Vitro¹

Department of Microbiology, University of Mississippi School of Medicine, Jackson, Mississippi, 39216

The aim of this work is the inhibition of pyrimidine catabolism in mammals, so that physiologically effective levels in circulating thymidine may be maintained. Dihydropyrimidine dehydrogenase was purified from rat and hamster livers, and various 5-substituted pyrimidines were tested as substrates. 5-Cyanouracil was reduced vigorously by enzyme from hamsters but only weakly by enzyme from rats; other analogs did not show this marked species difference. When 5-cyanouracil and uracil were tested together with the rat enzyme, the former blocked almost completely the reduction of uracil, which suggests that it is a good candidate for in vivo studies.

¹ Supported by American Cancer Society grant T-357 and Faculty Research Associate Award PR-40 (P. A. M.), and USPHS training grant AI-69 and awards 5-K3-AI-7021 (G. A. G.) and 1-F1-GM-33650 (M. T. D.).

² Submitted to the University of Mississippi in partial fulfillment of the requirements for the Doctor of Philosophy degree.

Received 5/16/68. Accepted 9/10/68.