Abnormalities in uridine homeostatic regulation and pyrimidine nucleotide metabolism as a consequence of the deletion of the uridine phosphorylase gene
Abnormalities in uridine homeostatic regulation and pyrimidine nucleotide metabolism as a consequence of the deletion of the uridine phosphorylase gene
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DOI：
10.1074/jbc.m412343200
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发表时间：
2005-06-03
影响因子：
4.8
通讯作者：
Pizzorno, G
中科院分区：
文献类型：
--
作者：
Cao, DL;Leffert, JJ;Pizzorno, G
在本研究中，我们报道了尿苷磷酸化酶（UPase）在尿苷稳态调节和嘧啶核苷酸代谢中的关键作用，采用新开发的UPase-/-小鼠。我们的数据表明，与野生型小鼠相比，UPase活性的消除导致血浆中尿苷浓度增加6倍以上，肺和肠道中尿苷浓度增加5-6倍，肝脏和肾脏中尿苷浓度增加2-3倍。在UPase-/-小鼠中尿尿水平增加了24倍。尿苷的半衰期和药理学剂量尿苷的血浆滞留明显延长。此外，在这些UPase-/-小鼠中，尿苷代谢异常导致各种核苷酸代谢紊乱。在UPase-/-小鼠的肝脏、肠道、肾脏和肺中，总尿苷核糖核苷酸浓度比对照小鼠增加2-3倍。胞苷核糖核苷酸、腺苷和鸟苷核糖核苷酸在这些器官中也有所增加，尽管程度较轻。UPase-/-小鼠的肠道和肺部出现了最显著的脱氧核糖核苷酸变化。在这些组织中，dTTP浓度增加了正常的4倍以上，dCTP、dGTP和dATP浓度增加了正常的1-2倍。肾脏dTTP浓度升高2倍，dCTP和dGTP浓度升高不足正常的1倍。此外，尿苷在血浆和组织中的积累有效地降低了5-氟尿嘧啶对宿主的毒性，改变了戊巴比妥的麻醉效果。这些数据表明，UPase是调节尿苷稳态和嘧啶核苷酸代谢以及5-氟尿嘧啶活性的关键酶。
We report in the present study the critical role of uridine phosphorylase (UPase) in uridine homeostatic regulation and pyrimidine nucleotide metabolism, employing newly developed UPase-/- mice. Our data demonstrate that the abrogation of UPase activity led to greater than a 6-fold increase in uridine concentrations in plasma, a 5-6-fold increase in lung and gut, and a 2-3-fold increase in liver and kidney, as compared with wild type mice. Urine uridine levels increased 24-fold normal in UPase-/- mice. Uridine half-life and the plasma retention of pharmacological doses of uridine were significantly prolonged. Further, in these UPase-/- mice, abnormal uridine metabolism led to disorders of various nucleotide metabolisms. In the liver, gut, kidney, and lung of UPase-/- mice, total uridine ribonucleotide concentrations increased 2-3 times as compared with control mice. Cytidine ribonucleotides and adenosine and guanosine ribonucleotides also increased, although to a lesser extent, in these organs. Most significant deoxyribonucleotide changes were present in the gut and lung of UPase-/- mice. In these tissues, dTTP concentration increased more than 4-fold normal, and dCTP, dGTP, and dATP concentrations rose 1-2 times normal. In kidney, dTTP concentration increased 2-fold normal, and dCTP and dGTP concentrations rose less than 1-fold normal. In addition, the accumulated uridine in plasma and tissues efficiently reduced 5-fluorouracil host toxicity and altered the anesthetic effect of pentobarbital. These data indicate that UPase is a critical enzyme in the regulation of uridine homeostasis and pyrimidine nucleotide metabolism, and 5-fluorouracil activity.