Aminoimidazole carboxamide ribonucleoside toxicity: A model for study of pyrimidine starvation
Aminoimidazole carboxamide ribonucleoside toxicity: A model for study of pyrimidine starvation
复制标题
氨基咪唑甲酰胺核糖核苷毒性：嘧啶饥饿研究模型
DOI：
10.1002/jcp.1041070305
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发表时间：
1981
影响因子：
5.6
通讯作者：
E. Holmes
中科院分区：
文献类型：
--
作者：
C. Thomas;J. Meade;E. Holmes
氨基咪唑甲酰胺核苷（AIC-R）是一种嘌呤前体，对中国仓鼠成纤维细胞的生长具有双相作用。在200 μM AIC-R下，细胞生长几乎完全停滞，而在50和700 μM AIC-R下，细胞生长与不存在核苷时观察到的细胞生长相当。AIC-R产生的生长抑制是乳清酸磷酸核糖基转移酶-乳清酸脱羧酶（OPRT-ODC）反应抑制的结果，如UTP和CTP的细胞内浓度降低87%、培养基中乳清酸盐蓄积以及通过在培养基中加入100 μM尿苷恢复正常生长所证明。在200 μM AIC-R下抑制嘧啶核苷酸合成与细胞内PP-核糖-P浓度降低82%和嘌呤核苷酸浓度增加150%相关。在700 μM AIC-R-a条件下细胞生长恢复至正常速率，在此条件下PP-核糖-P仍被抑制，嘌呤核苷酸浓度也被抑制（对照的40%）-在50 μM AIC-R条件下无毒性-嘌呤核苷酸浓度增加150%且PP-核糖-P浓度正常-表明在200 μM AIC-R下观察到的OPRT-ODC抑制是由PP-核糖-P减少和嘌呤核苷酸增加的组合引起的。这些研究提供了对细胞中OPRT-ODC反应控制的更好理解，并提供了对嘌呤核苷诱导的嘧啶饥饿基础的额外见解。
Aminoimidazole carboxamide ribonucleoside (AIC‐R), a purine precursor, has biphasic effects on the growth of Chinese hamster fibroblasts. At 200 μM AIC‐R cell growth is almost completely arrested, while at 50 and 700 μM AIC‐R cell growth is comparable to that observed in the absence of nucleoside. The growth inhibition produced by AIC‐R is the consequence of inhibition of the orotate phosphoribosyltransferase‐orotidylic decarboxylase (OPRT‐ODC) reactions, as evidenced by a 87% reduction in the intracellular concentrations of UTP and CTP, accumulation of orotate in the medium, and restoration of normal growth by inclusion of 100 μM uridine in the medium. Inhibition of pyrimidine nucleotide synthesis at 200 μM AIC‐R is associated with an 82% reduction in the intracellular concentration of PP‐ribose‐P and a 150% increase in the concentration of purine nucleotides. Restoration of cell growth to a normal rate at 700 μM AIC‐R—a condition under which PP‐ribose‐P remains depressed and purine nucleotide concentrations are also depressed (40% of control)—and absence of toxicity at 50 μM AIC‐R—a condition under which purine nucleotide concentrations are increased by 150% and PP‐ribose‐P concentration is normal—suggest that the inhibition of OPRT‐ODC observed at 200 μM AIC‐R is caused by the combination of the reduction in PP‐ribose‐P and increase in purine nucleotides. These studies provide a better understanding of the control of the OPRT‐ODC reactions in the cell and provide additional insight into the basis of pyrimidine starvation induced by purine nucleosides.