Sokoloski J A, Sartorelli A C
Mol Pharmacol. 1985 Dec;28(6):567-73.
The effects of the inhibitors of IMP dehydrogenase, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and mycophenolic acid, on the synthesis of cellular glycoproteins were evaluated in Sarcoma 180 cells. Both tiazofurin and mycophenolic acid decreased the rate of incorporation of [2-3H]mannose and [2-3H]fucose into acid-precipitable glycoproteins within 4 hr of exposure; this inhibitory activity was concentration dependent and occurred in the absence of a significant effect on the incorporation of labeled glucosamine and leucine into acid-insoluble material. Interference with the utilization of [3H]mannose for the formation of glycoproteins was paralleled by an inhibition of [3H] mannose incorporation into their lipid-linked oligosaccharide precursors following treatment with cytotoxic concentrations of tiazofurin (100 microM) or mycophenolic acid (10 microM); these actions occurred within 3 hr of exposure to these agents, with maximal reductions being observed at 12 hr. Under these conditions, intracellular GTP levels were reduced by 80%, whereas ATP pools remained unaffected ant UTP levels were markedly increased. Guanosine (100 microM) prevented the cytotoxic actions of tiazofurin and mycophenolic acid and reversed the drug-induced decrease in GTP pools and in the incorporation of mannose and other metabolic precursors into acid-insoluble material. Inhibition of fucose and mannose incorporation into lipid-linked oligosaccharides and glycoproteins were preceded by decreases in the labeling of their respective guanosine nucleotide sugars and were followed sequentially by alterations in the plasma membrane as detected by both the binding and the rate of cell agglutination caused by the plant lectin, concanavalin A. The findings that tiazofurin and mycophenolic acid produce alterations in the utilization of [3H]mannose for the formation of glycoproteins and in membrane architecture are indicative of metabolic lesions induced by agents that selectively depress guanine nucleotide synthesis through inhibition of IMP dehydrogenase.
在肉瘤180细胞中评估了肌苷5'-单磷酸脱氢酶抑制剂噻唑呋林（2-β-D-呋喃核糖基噻唑-4-甲酰胺）和霉酚酸对细胞糖蛋白合成的影响。噻唑呋林和霉酚酸在暴露4小时内均降低了[2-³H]甘露糖和[2-³H]岩藻糖掺入酸沉淀糖蛋白的速率；这种抑制活性呈浓度依赖性，并且在对标记的葡糖胺和亮氨酸掺入酸不溶性物质没有显著影响的情况下发生。用细胞毒性浓度的噻唑呋林（100μM）或霉酚酸（10μM）处理后，[³H]甘露糖掺入糖蛋白形成过程受到干扰，同时[³H]甘露糖掺入其脂质连接寡糖前体也受到抑制；这些作用在接触这些药物3小时内发生，在12小时时观察到最大程度的降低。在这些条件下，细胞内GTP水平降低了80%，而ATP池未受影响，UTP水平显著升高。鸟苷（100μM）可防止噻唑呋林和霉酚酸的细胞毒性作用，并逆转药物诱导的GTP池减少以及甘露糖和其他代谢前体掺入酸不溶性物质的减少。岩藻糖和甘露糖掺入脂质连接寡糖和糖蛋白受到抑制之前，其各自的鸟苷核苷酸糖的标记减少，随后通过植物凝集素伴刀豆球蛋白A引起的结合和细胞凝集速率检测到质膜发生改变。噻唑呋林和霉酚酸在[³H]甘露糖用于糖蛋白形成的利用以及膜结构方面产生改变，这些发现表明通过抑制肌苷5'-单磷酸脱氢酶选择性抑制鸟嘌呤核苷酸合成的药物诱导了代谢损伤。
