Shopsis C
Department of Chemistry, Adelphi University, Garden City, New York 11530.
Cell Biol Toxicol. 1994 Jun;10(3):191-205. doi: 10.1007/BF00757562.
Studies on the antagonism of toxicity can provide information about toxic mechanisms and suggest chemotherapeutic strategies. A rapid cell growth assay that measures the effects of test agents on the accumulation of cell protein (Shopsis and Eng, Toxicol. Lett. 1985;26:1) has been applied to studies of the antagonism of the cytotoxicity of cadmium. Exposure of Balb/c mouse 3T3 cells to 15 mumol/L Cd2+ for 24 h or 7 mumol/L Cd2+ for 48 h caused a 50% decrease in total cell protein. Zn2+ and selenite ion, antagonists of Cd toxicity in vivo, antagonized Cd2+ cytotoxicity when added in micromolar concentrations at the initiation of exposure to Cd2+. A diverse group of chemicals that can induce differentiation in vitro in cultured erythroleukemia and other cells were also found to antagonize the cytotoxic effects of Cd2+ to 3T3 cells. Dimethyl sulfoxide (DMSO), hexamethylene bisacetamide, N,N-dimethyl formamide, N-methyl formamide, dimethyl acetamide, hypoxanthine, hemin, ouabain, and sodium butyrate, when added to cultures simultaneously with Cd2+, each antagonized Cd2+ toxicity. These agents were used at concentrations equal to or lower than the concentrations at which they induce cellular differentiation. Other cytotoxicity assays and morphological studies confirmed these observations. DMSO added as much as 6 h after the initiation of a 24-h exposure to Cd2+ still protected cells; conversely, pretreatment of cultures with butyrate or DMSO for 24 h followed by their removal did not confer protection against subsequent Cd2+ challenge. Ethanol and methanol (noninducers of differentiation) did not antagonize Cd2+ cytotoxicity, and differentiation-inducing agents did not protect the cells from Zn(2+)- or Hg(2+)-induced cytotoxicity. DMSO treatment does not induce an increase in the concentrations of metallothionein or glutathione in these cells.
毒性拮抗作用的研究可以提供有关毒性机制的信息，并为化疗策略提供建议。一种快速细胞生长测定法，可测量受试物对细胞蛋白质积累的影响（Shopsis和Eng，《毒理学快报》，1985年；26:1），已应用于镉细胞毒性拮抗作用的研究。将Balb/c小鼠3T3细胞暴露于15 μmol/L Cd2+ 24小时或7 μmol/L Cd2+ 48小时，导致细胞总蛋白减少50%。锌离子和亚硒酸根离子是体内镉毒性的拮抗剂，在接触镉开始时以微摩尔浓度添加时，可拮抗Cd2+的细胞毒性。还发现一组能在体外诱导培养的红白血病细胞和其他细胞分化的化学物质也能拮抗Cd2+对3T3细胞的细胞毒性作用。二甲基亚砜（DMSO）、六亚甲基双乙酰胺、N，N-二甲基甲酰胺、N-甲基甲酰胺、二甲基乙酰胺、次黄嘌呤、血红素、哇巴因和丁酸钠，当与Cd2+同时添加到培养物中时，均可拮抗Cd2+的毒性。这些试剂的使用浓度等于或低于它们诱导细胞分化的浓度。其他细胞毒性测定和形态学研究证实了这些观察结果。在24小时暴露于Cd2+开始后长达6小时添加DMSO仍能保护细胞；相反，用丁酸盐或DMSO预处理培养物24小时后将其去除，并不能使细胞免受随后Cd2+攻击的保护。乙醇和甲醇（非分化诱导剂）不能拮抗Cd2+的细胞毒性，分化诱导剂也不能保护细胞免受Zn(2+)或Hg(2+)诱导的细胞毒性。DMSO处理不会导致这些细胞中金属硫蛋白或谷胱甘肽浓度的增加。
