Klein A K, Nasr M L, Goldman M
Laboratory for Energy-Related Health Research, University of California, Davis 95616.
Toxicol Lett. 1987 Oct;38(3):239-49. doi: 10.1016/0378-4274(87)90004-x.
Large amounts of the nerve agents, sarin (GB) and soman (GD), are part of the military chemical arsenal and small amounts are on hand in numerous U.S. research laboratories. Thus, there is a potential for accidental occupational exposure to these compounds. As part of a study of mutagenic, reproductive and subchronic effects of these agents, we measured unscheduled DNA repair synthesis in isolated rat hepatocytes after exposure to GBI (stabilized with tributylamine), GBII (stabilized with diisopropylcarbodiimide) or GD. This was done to determine whether these agents or their metabolites directly damage DNA or their related proteins. Each agent was assayed at least once over concentrations ranging from 3.0 X 10(-4) to 2.4 X 10(-3) M for GBI and GBII and 2.3 X 10(-4) to 1.8 X 10(-3) for GD and at least 3 times at 2.4 X 10(-3) M for GBI and GBII and 1.8 X 10(-3) M for GD, added as 20% of the culture medium. In all assays, no increase in the level of DNA synthesis was observed. On the contrary, significant decreases in repair synthesis were seen in hepatocytes exposed to GBI or GBII. The decreases in DNA synthesis seen in response to GD were less marked and not significant. These observations were not related to cell death, since 8 of 10 assays performed showed no significant decrease in the amount of DNA present in cultures exposed to the nerve agents compared to the negative controls. Our results suggest that the agents GBI, GBII and GD may either inhibit the repair of DNA or protect DNA from damage.
大量的神经性毒剂沙林（GB）和梭曼（GD）是军事化学武器库的一部分，美国众多研究实验室中也存有少量此类毒剂。因此，存在这些化合物意外职业暴露的可能性。作为对这些毒剂的致突变、生殖和亚慢性影响研究的一部分，我们在分离的大鼠肝细胞暴露于GBI（用三丁胺稳定）、GBII（用二异丙基碳二亚胺稳定）或GD后，测量了其非程序性DNA修复合成。这样做是为了确定这些毒剂或其代谢产物是否直接损伤DNA或其相关蛋白质。每种毒剂在GBI和GBII浓度范围为3.0×10⁻⁴至2.4×10⁻³M、GD浓度范围为2.3×10⁻⁴至1.8×10⁻³M时至少进行了一次测定，在GBI和GBII浓度为2.4×10⁻³M、GD浓度为1.8×10⁻³M时至少进行了3次测定，以培养基的20%添加。在所有测定中，未观察到DNA合成水平增加。相反，在暴露于GBI或GBII的肝细胞中，修复合成显著降低。对GD反应中观察到的DNA合成降低不太明显且不显著。这些观察结果与细胞死亡无关，因为与阴性对照相比，在暴露于神经性毒剂的培养物中进行的10次测定中有8次显示DNA含量没有显著降低。我们的结果表明，GBI、GBII和GD毒剂可能抑制DNA修复或保护DNA免受损伤。
