Cross-resistance of cadmium-resistant cells to manganese is associated with reduced accumulation of both cadmium and manganese
Cross-resistance of cadmium-resistant cells to manganese is associated with reduced accumulation of both cadmium and manganese
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DOI：
10.1016/j.tox.2010.12.002
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发表时间：
2011-02-27
期刊：
影响因子：
4.5
通讯作者：
Himeno, Seiichiro
中科院分区：
文献类型：
--
作者：
Fujishiro, Hitomi;Kubota, Keisuke;Himeno, Seiichiro
镉进入细胞的机制尚不清楚。我们之前已经从金属硫蛋白（MT）缺失的小鼠胚胎细胞中建立了抗镉细胞，并证明锌转运蛋白Zrt/ irt相关蛋白（ZIP） 8的下调是导致镉进入细胞减少的原因。在本研究中，我们从表达mt的野生型小鼠胚胎细胞中培育出抗镉细胞(A（+)70和B(+)70）。A(+)70和B(+)70细胞的CdCl2 LC50值约为200 μ M，亲本细胞的LC50值为30 μ M。我们发现这些细胞的抗镉性不仅与MT表达增强有关，还与镉积累减少有关。由于A(+)70和B(+)70细胞对镉的摄取速率降低，我们测定了可能参与细胞对镉摄取的金属转运体和通道的表达水平。我们发现，在a(+)70和B(+)70细胞中，多种运输系统，包括ZIP8、二价金属转运蛋白1 （DMT1）和l型（Ca(v)1.2）和t型（Ca(v)3.1）电压依赖性钙通道的α(1)亚基下调。此外，A(+)70和B(+)70细胞对MnCl2的细胞毒性表现出交叉抗性，可能是由于这些细胞对锰的摄取明显减少。这些结果表明，ZIP8和DMT1的表达被抑制可能是导致A(+)70和B(+)70细胞对镉和锰的摄取减少，从而降低细胞毒性的原因。ZIP8和DMT1已知对镉和锰具有亲和力。2010爱思唯尔爱尔兰有限公司版权所有。
The mechanism of cellular entry of cadmium remains unclear. We have previously established cadmium-resistant cells from mouse embryonic cells of metallothionein (MT)-null mice, and demonstrated that the down-regulation of a zinc transporter, Zrt/Irt-related protein (ZIP) 8, was responsible for the reduced cadmium incorporation into cells. In the present study, we developed cadmium-resistant cells (A(+)70 and B(+)70) from mouse embryonic cells of MT-expressing wild-type mice. The LC50 values of CdCl2 for A(+)70 and B(+)70 cells were about 200 mu M while that of the parental cells was 30 mu M. We found that the cadmium resistance of these cells was conferred not only by enhanced expression of MT, but also by a decrease in cadmium accumulation. Since the uptake rates of cadmium into A(+)70 and B(+)70 cells were lowered, we determined the expression levels of the metal transporters and channels potentially involved in the cellular uptake of cadmium. We found a down-regulation of multiple transport systems, including ZIP8, divalent metal transporter 1 (DMT1), and alpha(1) subunits of L-type (Ca(v)1.2) and T-type (Ca(v)3.1) voltage-dependent calcium channels, in A(+)70 and B(+)70 cells. Furthermore, A(+)70 and B(+)70 cells exhibited cross-resistance to cytotoxicity of MnCl2, probably due to a marked decrease in manganese uptake in these cells. These results suggest that the suppressed expression of ZIP8 and DMT1, which are known to have affinities for both cadmium and manganese, may be responsible for the reduction in the uptake, and consequently the cytotoxicity, of cadmium and manganese in A(+)70 and B(+)70 cells. (C) 2010 Elsevier Ireland Ltd. All rights reserved.