Onfelt A
Mutat Res. 1987 Jun;182(3):155-72.
The glutathione-specific agents diamide, diethyl maleate and 1-chloro-2,4-dinitrobenzene were found to induce a low frequency of c-mitosis (15%) at non-toxic concentrations concomitant with a 30-40% decrease of non-protein sulfhydryls. The frequency of c-mitosis did not increase further with increased concentrations until non-protein sulfhydryl levels were obtained suggesting depletion of reduced glutathione. The observed shape of the concentration-response curve for c-mitosis is particular to these 3 agents and caffeine among 22 different compounds being tested under comparable conditions. This suggests a similar mechanism of action and from what is known about caffeine this mechanism probably involves an impaired control of cytoplasmic free Ca2+. It is speculated that this impairment with the glutathione-specific agents is primarily due to depletion of a particular pool of reduced glutathione. Tertiary butylhydroperoxide which is a substrate for glutathione peroxidase(s) also causes c-mitosis when there is no significant decrease of non-protein sulfhydryls. The c-mitotic response was found to be biphasic with maintained control levels at an intermediate concentration. The humps in the concentration-response curve for c-mitosis appeared coincident with a mitogenic response (G1----S). Since the latter type of effect most probably is Ca2+ dependent and since the spindle is sensitive to Ca2+ it is tentatively suggested that the c-mitotic effect of tertiary butylhydroperoxide is due to an increase of cytoplasmic Ca2+. Measurements performed imply that an increase of glutathione disulfide (diamide) is more inhibitory to uptake and incorporation of thymidine than a decrease of reduced glutathione per se (diethyl maleate). This difference is probably due to secondary effects on pertinent protein sulfhydryls with diamide, one possible target being the ribonucleotide reductase. All compounds were found to cause an increase of ATP with some of the applied concentrations. The results with diethyl maleate suggest that an increase of ATP is favored by an attack on mitochondrial reduced glutathione. The possible analogy between this effect and an increase of ATP and Ap4A in bacteria during oxidative stress is considered.
谷胱甘肽特异性试剂二酰胺、马来酸二乙酯和1-氯-2,4-二硝基苯在无毒浓度下可诱导低频率的c-有丝分裂（15%），同时非蛋白巯基减少30 - 40%。随着浓度增加，c-有丝分裂频率并未进一步升高，直到非蛋白巯基水平下降，提示还原型谷胱甘肽耗竭。在可比条件下测试的22种不同化合物中，观察到的c-有丝分裂浓度-反应曲线形状是这3种试剂和咖啡因所特有的。这表明它们具有相似的作用机制，从已知的咖啡因作用机制来看，这种机制可能涉及细胞质游离Ca2+的调控受损。据推测，谷胱甘肽特异性试剂造成的这种损害主要是由于特定池的还原型谷胱甘肽耗竭。谷胱甘肽过氧化物酶的底物叔丁基过氧化氢在非蛋白巯基无显著下降时也会引起c-有丝分裂。发现c-有丝分裂反应呈双相性，在中间浓度时保持对照水平。c-有丝分裂浓度-反应曲线的峰值与促有丝分裂反应（G1期至S期）同时出现。由于后一种效应很可能依赖Ca2+，且纺锤体对Ca2+敏感，因此初步认为叔丁基过氧化氢引起的c-有丝分裂效应是由于细胞质Ca++增加所致。所进行的测量表明，二酰胺导致的谷胱甘肽二硫化物增加对胸苷摄取和掺入的抑制作用比马来酸二乙酯导致的还原型谷胱甘肽本身减少更明显。这种差异可能是由于二酰胺对相关蛋白巯基的继发效应，一个可能的靶点是核糖核苷酸还原酶。发现所有化合物在某些应用浓度下都会导致ATP增加。马来酸二乙酯的结果表明，攻击线粒体还原型谷胱甘肽有利于ATP增加。考虑了这种效应与氧化应激期间细菌中ATP和Ap4A增加之间可能的相似性。
