Olive P L
Chem Biol Interact. 1979 Oct;27(2-3):281-90. doi: 10.1016/0009-2797(79)90132-7.
The preferential sensitivity of hypoxic cells to nitroheteroxycles is thought to result from the actions of toxic intermediates of drug reduction produced under hypoxic conditions. However, a lack of oxygen also alters the biochemical state of the cell and may indirectly enhance the sensitivity, of hypoxic cells to these drugs. This hypothesis was tested by 'conditioning' mouse L-929 cells in oxygen-free buffer, then exposing the cells to nitrofurazone under both aerobic and anaerobic conditions. After conditioning, the rate of cell inactivation by nitrofurazone was equal in air or nitrogen-equilibrated buffer. Pretreatment of cells in 1 muM rotenone or 0.5 mM 2,4-dinitrophenol for one hour under aerobic conditions increased the sensitivity of the cells to nitrofurazone under aerobic conditions. Similar rates of cell killing were obtained when mouse L-cells were heated in buffer for 30 min at 43 degrees before incubation with nitrofurazone in either air or nitrogen. Also, incubation of cells with nitrofurazone in the presence of 0.1% glucose, or at a cell density less than 10(5) cells/ml significantly enhanced cell killing, especially under aerobic conditions. Thus, the intracellular state of the cell, manipulated by altering the cellular environment, influenced the cellular sensitivity to nitrofurazone. Similar results were not, however, obtained with the nitroimidazoles, dimetronidazole and misonidazole; pretreatment for 2 h in buffer under anaerobic conditions did not increase the sensitivity of L cells to subsequent drug treatment in air-equilibrated buffer.
低氧细胞对硝基杂环类药物的优先敏感性被认为是由低氧条件下产生的药物还原毒性中间体的作用所致。然而，缺氧也会改变细胞的生化状态，并可能间接增强低氧细胞对这些药物的敏感性。通过在无氧缓冲液中“预处理”小鼠L-929细胞，然后在需氧和厌氧条件下将细胞暴露于呋喃西林来验证这一假设。预处理后，在空气或氮气平衡缓冲液中，呋喃西林使细胞失活的速率是相同的。在需氧条件下，用1μM鱼藤酮或0.5 mM 2,4-二硝基苯酚预处理细胞1小时，可增加细胞在需氧条件下对呋喃西林的敏感性。当小鼠L细胞在缓冲液中于43℃加热30分钟，然后在空气或氮气中与呋喃西林孵育时，也获得了相似的细胞杀伤率。此外，在0.1%葡萄糖存在下或细胞密度低于10⁵个细胞/ml时，用呋喃西林孵育细胞可显著增强细胞杀伤作用，尤其是在需氧条件下。因此，通过改变细胞环境来操控细胞的胞内状态，会影响细胞对呋喃西林的敏感性。然而，对于硝基咪唑类药物甲硝唑和咪康唑，并未得到类似结果；在厌氧条件下于缓冲液中预处理2小时，并未增加L细胞对随后在空气平衡缓冲液中药物处理的敏感性。
