Studies on Uracil Utilization in Normal and Acetaminofluorene-treated Rats

Rutman, Robert J.; Cantarow, A.; Paschkis, K. E.; Allanoff, Betty

doi:10.1126/science.117.3037.282

Cited by 19 publications

(13 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the fact that the labelled uracil/dihydrouracil in the intact animals was not evenly distributed between blood and liver until 20min after injection, whereas that of the mice 6h after partial hepatectomy was so within 2min after injection, suggests a more efficient incorporation of these metabolites from blood into the regenerating liver. This interpretation of the results is in accordance with the better utilization of uracil known to occur in regenerating liver and hepatoma compared with normal liver (Rutman et al, 1954;Canellakis, 1957;Heidelberger et al, 1957).…”

Section: Discussionsupporting

confidence: 77%

Anabolism versus catabolism of [5-3H]uridine and its relationship to ribonucleic acid labelling in mouse liver after partial hepatectomy

Yngner

Engelbrecht

Lewan

et al. 1979

Biochemical Journal

View full text Add to dashboard Cite

The balance between anabolism and catabolism of [5-3H]uridine was studied in the mouse after partial hepatectomy. Labelling of RNA and UDP-glucose was determined and evaluated in relation to changes in the specific radioactivity of UTP. The amounts of labelled catabolic products of uridine were increased several-fold in liver and blood after partial hepatectomy. The specific radioactivity of RNA decreased to about 60% of the control value at 6h and was in the same range as that of control liver at 24h after operation. Decreased labelling of RNA and UDP-glucose was attributable to decreased specific radioactivity of UTP. No changes in the size of the UTP pool or in the balance between uridine anabolism and catabolism were found that could explain the decreased specific radioactivity of UTP. Rather, the alterations in the labelling of this metabolite induced by the partial hepatectomy may be related to decreased phosphorylating capacity in the liver cells and/or dilution of the labelled precursor in an expanded uridine pool. The enhanced amounts of uridine catabolic products in liver and blood were probably a consequence of accumulation and altered incorporation of the metabolites from the blood into the liver cells. Despite the increased amounts of labelled catabolic products and the decreased labelling of RNA, the results reported here actually suggest decreased uridine catabolism and slightly increased RNA synthesis in mouse liver after partial hepatectomy. The results stress the importance of proper controls in determination of nucleic acid synthesis and in metabolic studies by use of labelled precursors.

show abstract

Section: Discussionsupporting

confidence: 77%

Anabolism versus catabolism of [5-3H]uridine and its relationship to ribonucleic acid labelling in mouse liver after partial hepatectomy

Yngner

Engelbrecht

Lewan

et al. 1979

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Complete degradation of these drugs may likely involve the ring cleavage of the core structure of barbituric acid. Although so far there is no direct evidence of barbiturase activity or the existence of oxidative pyrimidine metabolism in mammals, some early articles reported that radioactive 15 N-or 14 C-urea, a possible product of oxidative but not reductive metabolism, was detected in the urine when 15 Nor 14 C-labeled uracil was intravenously administered to rats (47,48). However, further investigation has to be carried out to verify whether barbiturase or the oxidative pathway is functioning in mammals.…”

Section: Discussionmentioning

confidence: 99%

Barbiturase, a Novel Zinc-containing Amidohydrolase Involved in Oxidative Pyrimidine Metabolism

Soong¹,

Ogawa

Sakuradani³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Barbiturase, which catalyzes the reversible amidohydrolysis of barbituric acid to ureidomalonic acid in the second step of oxidative pyrimidine degradation, was purified to homogeneity from Rhodococcus erythropolis JCM 3132. The characteristics and gene organization of barbiturase suggested that it is a novel zinc-containing amidohydrolase that should be grouped into a new family of the amidohydrolases superfamily. The amino acid sequence of barbiturase exhibited 48% identity with that of herbicide atrazine-decomposing cyanuric acid amidohydrolase but exhibited no significant homology to other proteins, indicating that cyanuric acid amidohydrolase may have evolved from barbiturase. A putative uracil phosphoribosyltransferase gene was found upstream of the barbiturase gene, suggesting mutual interaction between pyrimidine biosynthesis and oxidative degradation. Metal analysis with an inductively coupled radiofrequency plasma spectrophotometer revealed that barbiturase contains ϳ4.4 mol of zinc per mol of enzyme. The homotetrameric enzyme had K m and V max values of 1.0 mM and 2.5 mol/min/mg of protein, respectively, for barbituric acid. The enzyme specifically acted on barbituric acid, and dihydro-L-orotate, alloxan, and cyanuric acid competitively inhibited its activity. The full-length gene encoding the barbiturase (bar) was cloned and overexpressed in Escherichia coli. The kinetic parameters and physicochemical properties of the cloned enzyme were apparently similar to those of the wild-type.In a biological system, pyrimidines are metabolized through either a reductive or an oxidative pathway (1, 2). It is well recognized that mammals, plants, and microorganisms utilize the reductive pathway for pyrimidine degradation (3-5), whereas some microorganisms use the oxidative pathway (6 -8).In reductive pyrimidine metabolism, uracil, or thymine is first reduced to its dihydro-derivative, which in turn is hydrolyzed to an N-carbamoyl-␤-amino acid and finally decarbamoylated to a ␤-amino acid. This metabolic route, especially the hydrolysis of dihydro-derivatives catalyzed by dihydropyrimidinase, has attracted much attention, because it is a potential target for drug therapy in the treatment of cancer (9, 10), and it also has been used for the industrial production of optically active amino acids (5,11,12). In contrast, oxidative pyrimidine metabolism has been scarcely investigated, and the references available so far are limited to the early studies performed by three groups of scientists (6 -8). These reports showed that pyrimidine bases are first oxidized to barbituric acid derivatives, and then the barbituric acid derivatives are further hydrolyzed by barbiturase (EC 3.5.2.1) to urea and malonate derivatives. However, these studies were carried out with crude enzyme preparations, and the results presented were inadequate for confirming the enzymatic conversion of barbituric acid to urea and malonate.We have elucidated the enzymes involved in the oxidative pathway, and clarified their physiological functions, in a ...

show abstract

“…From these observations we may conclude that the rate of uptake found in the in vivo experiments indicates only the average activity of the whole tumour and not the true activity of its most rapidly growing periphery. A similar view is put forward by Caspersson and Santesson (1942), and by Rutman et al (1954).…”

Section: Activity Of In Vitro Preparationsmentioning

confidence: 56%

A Biochemical Concept of Tumour Growth, Infiltration, and Cachexia

Wiseman¹,

Ghadially²

1958

BMJ

View full text Add to dashboard Cite

MBmicTJo= oestrogen excreted by the four patients who failed to benefit from operation (Table II) was 7 ,ug./24 hours-a value slightly higher than the mean level for all patients in this category, and higher than the mean pre-operative level of patients obtaining remission at hypophysectomy (Table 1). There are not enough patients in the series for these findings to have any statistical significance, but there may be a tendency for patients with a low pre-operative oestrogen level to benefit from hypophysectomy while those with a high level do not. Further work is needed to check the validity of this suggestion.In two instances patients who had been previously treated by oophorectomy and adrenalectomy were subjected to hypophysectomy. In neither case was oestrogen detected in the urine either before or after hypophysectomy, yet in both patients their objective regressions were short. Unless they were excreting amounts of oestrogen not detectable by the chemical method, these results suggest a direct participation of pituitary hormones in the maintenance of human breast cancer, as opposed to an indirect trophic effect on target organs. Similarly, in the patient already referred to (Case 7) objective regression occurred in spite of continued oestrogen excretion. Again, this result is explicable on the assumption that the levels of growth hormone, prolactin, or both had been reduced below a critical level.In the four patients referred to in Table II the most simple explanation for the failure of hypophysectomy to influence the growth of the breast cancer is the continued excretion of oestrogens due to incomplete hypophysectomy.We have, as yet, been unable to study the transition from remission to relapse in this series. However, Hortling et al.(1957), using the vaginal-smear technique, found that oestrogen secretion increased simultaneously with the deterioration of the patient's clinical condition.The explanation of failure or success following endocrine ablation for breast cancer must be largely speculative until we are able to assess directly the functional capacity of the human hypophysis with a reasonable degree of precision.The results of the investigations on the small number of patients in the present series suggest that repeated biochemical estimation of oestrogens before hypophysectomy may prove to be of some value in forecasting the clinical outcome of this operation.Continued post-operative excretion of oestrogen, by indicating incomplete removal, suggests that no significant clinical palliation is likely to occur, while cessation of oestrogen excretion would suggest the reverse. The exceptions to these generalizations provide cogent reasons for supposing that the growth of some human breast cancers is maintained by the direct action on the tumour cells of anterior pituitary hormones. Summary The effect of hypophysectomy on the clinical state and on oestrogen excretion has been studied in 15 women and one man with metastatic breast cancer.Patients obtaining regression following hypophysectomy tended to ...

show abstract

Studies on Uracil Utilization in Normal and Acetaminofluorene-treated Rats

Cited by 19 publications

References 13 publications

Anabolism versus catabolism of [5-3H]uridine and its relationship to ribonucleic acid labelling in mouse liver after partial hepatectomy

Anabolism versus catabolism of [5-3H]uridine and its relationship to ribonucleic acid labelling in mouse liver after partial hepatectomy

Barbiturase, a Novel Zinc-containing Amidohydrolase Involved in Oxidative Pyrimidine Metabolism

A Biochemical Concept of Tumour Growth, Infiltration, and Cachexia

Contact Info

Product

Resources

About