Effect of 5-benzylacyclouridine, a potent inhibitor of uridine phosphorylase, on the metabolism of circulating uridine by the isolated rat liver
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Uridine triphosphate
Twenty millimolar and 2 mm uridine triphosphate and 2 mm uridine were injected intra-arterially into rat leg muscles during a 20 min period of intense exercise and during the recovery phase (20 min).Administration of 20 mm uridine triphosphate during exercise, provoked a complete depression of muscle contractility. On the contrary, supply of 2 mm uridine triphosphate or 20 mm uridine induced a reduction in the decrease of muscular developed tension during the exercise period of time and favoured functional recovery.This positive effect of pyrimidine compounds on muscular functional parameters did not seem to be correlated with metabolic effects. Indeed, 2 mm uridine supply did not modify the evolution of intramuscular glycogen and lactate concentrations and made worsened the adenine nucleotide degradation induced by exercise.
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Previous results from our laboratory have shown that the nucleoside transport inhibitor dipyridamole (DP) markedly augmented both the in vitro and in vivo activities of the pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA). In a human ovarian carcinoma cell line (2008), DP increased the activity of PALA by 1 to 2 logs in growth rate and clonogenic assays while exhibiting no cytotoxicity of its own. The concentration of DP used (1 microM) in these assays resulted in over 80% reduction in uridine uptake in the 2008 cells at the end of 1 h. The activity of PALA and PALA plus DP was completely antagonized by the addition of exogenous uridine in a dose-dependent manner. Addition of other nucleosides to concentrations as high as 1000 microM failed to rescue the ovarian cells from the drug combination, and combining two nucleosides together did not antagonize PALA and PALA plus DP activity to any greater extent. Cellular nucleotide pool analysis by anion-exchange high-performance liquid chromatography revealed that dipyridamole further reduced the already depressed uridine triphosphate and cytidine triphosphate pools of cells exposed to PALA, while the guanosine triphosphate pool was slightly elevated. Uridine supplementation resulted in partial replenishment of the uridine triphosphate and cytidine triphosphate pools, but the absolute levels remained below control values. The acute drug-induced changes in nucleotide pools in 2008 xenografts growing in athymic mice paralleled those observed in vitro. Evidence presented here supports the ability of DP to potentiate PALA activity against a human ovarian carcinoma cell line. The mechanism of synergy relates to the inhibition of pyrimidine salvage in the tumor cells via the blockade of uridine uptake.
Uridine triphosphate
Cytidine
Uridine diphosphate
Clonogenic assay
Dipyridamole
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Uridine triphosphate
Nucleotide salvage
Cytidine
Nucleoside-diphosphate kinase
Nucleoside triphosphate
Ribonucleotide
Adenosine triphosphate
Pyrimidine metabolism
Uridine diphosphate
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Uridine triphosphate
Phosphoglucomutase
Uridine diphosphate glucose
Nucleotide salvage
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Neurite
Uridine triphosphate
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Uridine triphosphate
Uridine diphosphate
Ion chromatography
Nucleotide salvage
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Abstract Uridine 5′-O-triphosphate (UTP) is a potent agonist of the purinergic receptor designated P2Y2. UTP is rapidly metabolized in human tissue. To find a compound with similar activity that may be more slowly metabolized, a series of 4-substituted uridine 5′-triphosphates were prepared and evaluated in a P2Y2 receptor second messenger assay.
Uridine triphosphate
Uridine diphosphate
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Uridine triphosphate
Adenosine triphosphate
Anaerobic glycolysis
Creatine
Creatine kinase
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Uridine triphosphate
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The relation between cellular uracil nucleotides and ability to synthesize glycogen was studied in rat diaphragm incubated in vitro. In the absence of exogenous uridine the tissue content of UTP and rate of glycogen synthesis decreased with time. Uridine added to the medium increased cellular UTP and UDPG and stimulated glycogen synthesis. Insulin significantly increased the synthesis of UTP from extracellular uridine. This action of insulin appeared to be due to a stimulation of phosphorylation of the nucleoside and not to an effect on transport at the concentrations of uridine studied. However, an effect of insulin on transport of uridine at low concentrations cannot be excluded.
Uridine triphosphate
Uridine diphosphate glucose
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