Liebl B, Mückter H, Doklea E, Fichtl B, Forth W
Walther-Straub-Institut für Pharmakologie und Toxikologie, Universität München, Federal Republic of Germany.
Fundam Appl Toxicol. 1995 Aug;27(1):1-8. doi: 10.1006/faat.1995.1103.
It has been shown that oxophenylarsine (PhAsO) inhibits glucose uptake in MDCK cells. In addition to the known impairment of cellular energy metabolism, this inhibition may contribute to the acute toxicity of trivalent organic arsenicals. We have investigated the effect of BAL, DMPS, DMSA, and other sulfur compounds on cellular incorporation of [U-14C]PhAsO and their efficacy to revert PhAsO-induced inhibition of glucose uptake. In the presence of [U-14C]PhAsO (2 microM), the radiolabel was steadily accumulated by the cells over 150 min without any signs of severe cell damage (e.g., altered morphology, increased LDH release). A notable decrease of cellular ATP was only observed at 150 min, whereas within 30 min uptake of D-[6-(14)C]glucose was reduced to 40% of controls. When BAL, DMPS, or DMSA was added after 30 min, the inhibition of glucose uptake was reversed, accompanied by a decrease in cell-associated radiolabel from [U-14C]-PhAsO. Water-soluble DMPS and DMSA required longer times than BAL for comparable effects. 2,3-Bis(acetylthio)propanesulfonamide, a thioester derivative, and dithiothreitol, a 1,4-dithiol, were effective only with the highest concentration tested (200 microM). 2-Mercaptoethanol neither reversed inhibition of glucose uptake nor influenced [U-14C]PhAsO incorporation. Our results show that inhibition of glucose uptake is a very early event in PhAsO cytotoxicity which occurs before any decrease of cellular energy metabolism and/or full cellular loading with arsenic comes into effect. The more rapid onset of action of lipophilic BAL compared to PhAsO action.
已表明氧代苯胂（PhAsO）可抑制MDCK细胞对葡萄糖的摄取。除了已知的细胞能量代谢受损外，这种抑制作用可能导致三价有机砷化合物的急性毒性。我们研究了二巯丙醇（BAL）、二巯基丙磺酸钠（DMPS）、二巯基丁二酸（DMSA）和其他含硫化合物对[U-14C]PhAsO细胞摄取的影响，以及它们逆转PhAsO诱导的葡萄糖摄取抑制的效果。在存在[U-14C]PhAsO（2 microM）的情况下，放射性标记在150分钟内被细胞稳定积累，没有任何严重细胞损伤的迹象（如形态改变、乳酸脱氢酶释放增加）。仅在150分钟时观察到细胞ATP显著下降，而在30分钟内，D-[6-(14)C]葡萄糖的摄取降至对照的40%。当在30分钟后加入BAL、DMPS或DMSA时，葡萄糖摄取的抑制作用被逆转，同时细胞中与[U-14C]-PhAsO相关的放射性标记减少。水溶性的DMPS和DMSA达到类似效果所需的时间比BAL长。硫酯衍生物2,3-双（乙酰硫基）丙烷磺酰胺和1,4-二硫醇二硫苏糖醇仅在测试的最高浓度（200 microM）下有效。2-巯基乙醇既不能逆转葡萄糖摄取的抑制，也不影响[U-14C]PhAsO的摄取。我们的结果表明，葡萄糖摄取的抑制是PhAsO细胞毒性中非常早期的事件，发生在细胞能量代谢任何下降和/或细胞砷完全负载生效之前。亲脂性的BAL比PhAsO作用起效更快。
