Relative importance of transport and alkylation for pancreatic beta-cell toxicity of streptozotocin
Relative importance of transport and alkylation for pancreatic beta-cell toxicity of streptozotocin
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DOI：
10.1007/s001250051564
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发表时间：
2000-12-01
期刊：
影响因子：
8.2
通讯作者：
Lenzen, S
中科院分区：
文献类型：
--
作者：
Elsner, M;Guldbakke, B;Lenzen, S
目的/假设。通过比较链脲佐菌素与四种化学相关的烷基化化合物N-甲基-N-亚硝基脲（MNU）、N-乙基-N-亚硝基脲（ENU）甲磺酸甲酯（MMS）和甲磺酸乙酯（EMS）。通过稳定转染大鼠葡萄糖转运蛋白GLUT产生表达GLUT 2的RINm 5 F细胞; pcDNA 3载体中巨细胞病毒启动子控制下的cDNA。使用基于微量滴定板的3 - [4，5-二甲基噻唑-2-基]-2，5-二苯基溴化四唑（MTT）测定法测定细胞的活力。表达葡萄糖转运蛋白GLUT 2的细胞比对照细胞更容易受到链脲佐菌素毒性的影响，这是由于这种特异性葡萄糖转运蛋白对链脲佐菌素的摄取。相反，GLUT 2表达对MNU、ENU、MMS或EMS的毒性没有影响。虽然后者的物质，如链脲佐菌素，通过其导致DNA烷基化的能力，它们是细胞毒性的，但它们不是糖尿病原性的，因为它们不是通过葡萄糖转运蛋白GLU 2。结论/解释。我们的研究结果是一致的选择性摄取和烷基化活性的链脲佐菌素致糖尿病的机制中的核心重要性。DNA的烷基化导致胰腺β细胞坏死，从而导致胰岛素依赖性糖尿病的状态，在实验性糖尿病研究中被称为链脲佐菌素糖尿病。
Aims/hypothesis. The role of selective uptake and alkylation in the diabetogenic action of streptozotocin was investigated in bioengineered RINm5F insulin-producing cells, with different expression levels of the glucose transporter GLUT2, by comparing the toxicity of streptozotocin with that of four chemically related alkylating compounds, N-methyl-N-nitrosourea (MNU), N-ethyl-N nitrosourea (ENU), methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS).Methods. GLUT2 expressing RINm5F cells were generated through stable transfection of the rat glucose transporter GLUT;! cDNA under the control of the cytomegalovirus promoter in the pcDNA3 vector. Viability of the cells was determined using a microtitre plate-based 3 - [4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay.Results. Cells expressing the glucose transporter GLUT2 were much more susceptible to streptozotocin toxicity than control cells due to the uptake of streptozotocin by this specific glucose transporter. In contrast, the GLUT2 expression had no effect upon the toxicity of MNU, ENU, MMS or EMS. Although the latter substances are, like streptozotocin, cytotoxic through their ability to cause DNA alkylation, they are not diabetogenic because they are not taken up through the glucose transporter GLU2.Conclusion/interpretation. Our results are consistent with the central importance of selective uptake and alkylating activity in the mechanism of streptozotocin diabetogenicity. Alkylation of DNA leads to necrosis of pancreatic beta cells and thus to a state of insulin-dependent diabetes mellitus, well-known as streptozotocin diabetes in experimental diabetes research.