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The Effect of Dietary 2-Acetylaminofluorene on the Uracil-degrading Enzymes in Rat Liver¹

( Department of Biochemistry and Pathology, Norsk Hydro's Institute for Cancer Research, Montebello, Oslo, Norway)

The activities of the uracil-degrading liver enzymes, uracil reductase (EC 1.3.1.2), dihydrouracil hydrolase (EC 3.5.2.2), and carbamoyl-ß-alanine hydrolase (EC 3.5.1.6) have been determined in rats fed 2 different basal diets supplemented with the carcinogen 2-acetylaminofluorene for various lengths of time. A fall in the activities of all 3 enzymes occurred in the preneoplastic liver during carcinogen feeding. It was most pronounced in the case of uracil reductase, the enzyme which limits uracil breakdown in rat liver. The activities of uracil reductase and carbamoyl-ß-alanine hydrolase reached the minimum level in about 30 days. The dihydrouracil hydrolase activity decreased still more slowly. The enzymes remained at the low activity level or increased slowly in activity during continued carcinogen feeding. Removal of the carcinogen after 90 days resulted in almost complete recovery of the activities of all 3 enzymes.

With dietary supplements of 0.03 and 0.05% 2-acetylaminofluorene, the decrease in uracil reductase activity was proportional to the amount of carcinogen in the diet, the minimum level being about 50% of the control. The decrease in enzyme activity was the same with the 2 different basal diets, even though the rate of occurrence of malignant transformation was strikingly different with the 2 diets.

The results are discussed in relation to uracil incorporation into RNA,³ and to liver carcinogenesis. Possible factors responsible for the decrease in enzyme activity are considered.

¹ This work was supported by a grant from Norsk Hydro's Foundation.

³ Abbreviations used are: AAF, 2-acetylaminofluorene; RNA, ribonucleic acid; DNA, deoxyribonucleic acid; DHU, dihydrouracil; CBA, carbamoyl-ß-alanine; NADPH₂, nicotinamide adenine dinucleotide phosphate, reduced form.

² Fellow of the Norwegian Cancer Society (Landsforeningen mot Kreft).

Received 12/17/64.