Alteration in de novo pyrimidine biosynthesis during uridine reversal of pyrazofurin‐inhibited dna synthesis
作者:
David P. Ringer,
Boyd A. Howell,
Janet L. Etheredge,
期刊:
Journal of Biochemical Toxicology
(WILEY Available online 1991)
卷期:
Volume 6,
issue 1
页码: 19-27
ISSN:0887-2082
年代: 1991
DOI:10.1002/jbt.2570060104
出版商: Wiley Subscription Services, Inc., A Wiley Company
关键词: Pyrazofurin Metabolism;Salvage Pyrimidine Metabolism;De Novo Pyrimidine Metabolism;Concanavalin A;Guinea Pig Lymphocytes;DNA Synthesis;Intracellular Nucleoside Uptake;Uridine Reversal of Pyrazofurin
数据来源: WILEY
摘要:
AbstractPyrazofurin, a pyrimidine nucleoside analogue with antineoplastic activity, inhibits cell proliferation and DNA synthesis in cells by inhibiting uridine 5′‐phosphate (UMP) synthase. It has been previously shown in concanavalin A (con A)‐stimulated guinea pig lymphocytes (23) that pyrazofurininhibited DNA synthesis could be selectively reversed by exogenous uridine (Urd). In this report, we have examined possible mechanisms for the Urd reversal with experiments that determine the ability of exogenous Urd to (a) interfere with either the intracellular transport of pyrazofurin, or the conversion of pyrazofurin to its intracellularly active form, pyrazofurin‐5′‐phosphate; (b) reverse the pyrazofurin block of [14C]orotic acid incorporation into DNA; and (c) alter the pattern of exogenous [3H]Urd incorporation into DNA‐thymine (DNA‐Thy) and DNA‐cytosine (DNA‐Cyt) during pyrazofurin inhibition of pyrimidine de novo biosynthesis. The results of these experiments showed that Urd reversal does not occur through altered pyrazofurin transport or intracellular conversion to pyrazofurin‐5′‐phosphate, nor does it alter the distribution of [3H]Urd in DNA‐Thy and DNA‐Cyt. Instead, these findings indicate that the primary mechanism for exogenous Urd reversal of pyrazofurin inhibition of DNA synthesis involves the reversal of pyrazofurin inhibition of UMP synthase, thus restoring orotic acid incorporation into lymphocyte DNA through t
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