Thomas D J, Angle C R, Swanson S A, Caffrey T C
Department of Pediatrics, College of Medicine, University of Nebraska Medical Center, Omaha 68198.
Toxicology. 1991 Feb 11;66(1):35-46. doi: 10.1016/0300-483x(91)90176-2.
ROS 17/2.8 cells, a cloned rat osteosarcoma cell line, are exceptionally sensitive to the cytotoxic effects of cadmium. This sensitivity is associated with the inability of this metal to induce the synthesis of metallothionein, a transition metal-binding protein, which detoxifies this metal by its sequestration. Sodium butyrate induces the synthesis of metallothionein in these cells in a concentration-dependent manner. Treatment with this agent also significantly increases the resistance of these cells to the cytotoxic effects of cadmium and the protective effect of butyrate is reversed upon its removal from culture medium. Butyrate treatment did not significantly alter the accumulation of cadmium by these cells. Hence, the increased synthesis of metallothionein in butyrate-treated cells is not due to increased cellular uptake of cadmium. Inhibition of DNA synthesis due to butyrate was not a sufficient condition to alter metallothionein synthesis or to protect against Cd-induced cytotoxicity. Equivalent inhibition of DNA synthesis with hydroxyurea failed to increase metallothionein synthesis in cadmium-treated cells. These results indicate that modulation of metallothionein gene expression in this cell line is the critical factor in determining cellular sensitivity to the cytotoxic effects of cadmium.
ROS 17/2.8细胞是一种克隆的大鼠骨肉瘤细胞系，对镉的细胞毒性作用异常敏感。这种敏感性与该金属无法诱导金属硫蛋白（一种过渡金属结合蛋白）的合成有关，金属硫蛋白通过螯合作用使该金属解毒。丁酸钠以浓度依赖的方式诱导这些细胞中金属硫蛋白的合成。用该试剂处理也显著增加了这些细胞对镉细胞毒性作用的抗性，并且当从培养基中去除丁酸钠后，其保护作用会逆转。丁酸钠处理并未显著改变这些细胞对镉的积累。因此，丁酸钠处理的细胞中金属硫蛋白合成的增加并非由于细胞对镉摄取的增加。丁酸钠导致的DNA合成抑制并非改变金属硫蛋白合成或预防镉诱导的细胞毒性的充分条件。用羟基脲等效抑制DNA合成未能增加镉处理细胞中金属硫蛋白的合成。这些结果表明，该细胞系中金属硫蛋白基因表达的调节是决定细胞对镉细胞毒性作用敏感性的关键因素。
