Bao Yizhong, Wang Dan, Hu Yuxing, Xu Aihong, Chen Honghong
*Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China.
Health Phys. 2013 Jul 1;105(1):31-38. doi: 10.1097/HP.0b013e31828911a0.
In animal experiments, catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) was proven to be an effective chelator for the decorporation of uranium (U)(VI). In the present study, the authors investigated the molecular processes of CBMIDA-CaNa2 on the removal of U(VI) at the cellular level and explored its protective effects and mechanism against U(VI)-induced cell damage in HK-2 human renal proximal tubular cells. The results indicated that the chelating U(VI) effect of CBMIDA-CaNa2 was superior compared to that of DTPA-CaNa3; more specifically, at concentrations of 50 and 250 μM, CBMIDA-CaNa2 can significantly reduce U(VI) uptake and increase U(VI) release in U(VI)-exposed HK-2 cells after immediate or 24-h and 48-h delayed chelator administration better than those of DTPA-CaNa3. Furthermore, CBMIDA-CaNa2 significantly decreased the lactate dehydrogenase release and the formation of micronuclei and inhibited the production of intracellular reactive oxygen species (ROS) in HK-2 cells exposed to U(VI), whereas DTPA-CaNa3 was demonstrated to be ineffective. By reviewing the results of animal experiments conducted by several other investigators, including this lab, the authors found that removal efficacy and protective effects of these two chelators for U(VI) at the cellular level agreed well with those of animal studies. In addition, although U(VI) induced the increase of metallothionein protein expression in HK-2 cells, CBMIDA-CaNa2 can mobilize and remove the U(VI) from metallothionen (MT) after 48-h delayed chelator treatment. These results suggested that CBMIDA-CaNa2 protected against U(VI)-induced HK-2 cells damaged by reducing U(VI) uptake, increasing U(VI) release and scavenging the U(VI)-induced intracellular ROS.
在动物实验中，儿茶酚-3,6-双（甲基亚氨基二乙酸）（CBMIDA）被证明是一种有效的铀（U）（VI）促排螯合剂。在本研究中，作者在细胞水平上研究了CBMIDA-CaNa2去除U（VI）的分子过程，并探讨了其对U（VI）诱导的HK-2人肾近端小管细胞损伤的保护作用及机制。结果表明，CBMIDA-CaNa2的螯合U（VI）效果优于二乙三胺五乙酸钙三钠（DTPA-CaNa3）；更具体地说，在50和250 μM浓度下，CBMIDA-CaNa2在立即或延迟24小时和48小时给予螯合剂后，能比DTPA-CaNa3更显著地降低U（VI）暴露的HK-2细胞中U（VI）的摄取并增加U（VI）的释放。此外，CBMIDA-CaNa2显著降低了HK-2细胞中乳酸脱氢酶的释放和微核的形成，并抑制了暴露于U（VI）的HK-2细胞中细胞内活性氧（ROS）的产生，而DTPA-CaNa3则被证明无效。通过回顾包括本实验室在内的其他几位研究者进行的动物实验结果，作者发现这两种螯合剂在细胞水平上对U（VI）的去除效果和保护作用与动物研究结果高度一致。此外，尽管U（VI）诱导HK-2细胞中金属硫蛋白蛋白表达增加，但在延迟48小时给予螯合剂处理后，CBMIDA-CaNa2可以从金属硫蛋白（MT）中动员并去除U（VI）。这些结果表明，CBMIDA-CaNa2通过减少U（VI）摄取、增加U（VI）释放和清除U（VI）诱导的细胞内ROS来保护HK-2细胞免受U（VI）诱导的损伤。
