Tuttle S W, Biaglow J E, Varnes M E, Donahue L L, Clark E P, Epp E R
Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1161-4. doi: 10.1016/0360-3016(86)90249-x.
Chronic aerobic exposure of A549 human lung carcinoma cell cultures to 0.1 mM L-buthionine-S,R-sulfoximine and 1 mM misonidazole, or 1 mM SR-2508 results in inhibition of cell growth and decreased clonogenic survival. These patterns are not apparent with the individual drug treatments. Both parameters demonstrate maximum toxicity after 72 hr in culture, which parallels the time required to deplete A549 cells of glutathione with 0.1 mM L-BSO under these growth conditions. Toxicity appears to be related to hydrogen peroxide-produced during 1 electron reduction of the nitro compounds in the presence of oxygen. A549 cells have a lowered capacity to reduce peroxide due to the effect of thiol depletion on the enzymes GSH-peroxidase and GSH-S-transferase, which require the tripeptide as a substrate. The addition of catalase, another important enzyme involved in peroxide reduction, partially reverses the observed toxicity. 4-Hydroxypyrazole, which inhibits endogenous catalase activity, causes an increase in the observed cytotoxicity. Similar effects of L-BSO and 4-hydroxypyrazole are seen for toxicity due to hydrogen peroxide being added directly to cell cultures.
将A549人肺癌细胞培养物长期有氧暴露于0.1 mM L-丁硫氨酸-S，R-亚砜亚胺和1 mM米索硝唑或1 mM SR-2508会导致细胞生长受到抑制且克隆形成存活率降低。单独使用药物处理时，这些模式并不明显。在培养72小时后，这两个参数均显示出最大毒性，这与在这些生长条件下用0.1 mM L-BSO耗尽A549细胞谷胱甘肽所需的时间相当。毒性似乎与在有氧条件下硝基化合物单电子还原过程中产生的过氧化氢有关。由于硫醇耗竭对谷胱甘肽过氧化物酶和谷胱甘肽-S-转移酶（这两种酶需要三肽作为底物）的影响，A549细胞还原过氧化物的能力降低。添加过氧化氢酶（另一种参与过氧化物还原的重要酶）可部分逆转观察到的毒性。抑制内源性过氧化氢酶活性的4-羟基吡唑会导致观察到的细胞毒性增加。对于直接向细胞培养物中添加过氧化氢所导致的毒性，L-BSO和4-羟基吡唑也有类似的作用。
