MRP2 and the DMPS- and DMSA-mediated elimination of mercury in TR- and control rats exposed to thiol S-conjugates of inorganic mercury
MRP2 and the DMPS- and DMSA-mediated elimination of mercury in TR- and control rats exposed to thiol S-conjugates of inorganic mercury
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DOI：
10.1093/toxsci/kfn107
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发表时间：
2008-09-01
影响因子：
3.8
通讯作者：
Zalups, Rudolfs K.
中科院分区：
文献类型：
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作者：
Bridges, Christy C.;Joshee, Lucy;Zalups, Rudolfs K.
无机汞 (Hg(2+)) 的半胱氨酸 (Cys) 和高半胱氨酸 (Hcy)-S-结合物是 Hg(2+) 的可运输物质，很容易被近端肾小管细胞吸收。金属螯合剂 2,3-二巯基丙烷-1-磺酸 (DMPS) 和内消旋 2,3-二巯基琥珀酸 (DMSA) 已成功用于从这些细胞中提取 Hg(2+)，推测是通过多药耐药蛋白 (Mrp2)。在当前的研究中，我们测试了这样的假设：在给予作为Cys 或Hcy 的S-结合物的Hg(2+) 后，Mrp2 参与DMPS 和DMSA 介导的Hg(2+) 提取。为了检验这一假设，对照和TR(-)（Mrp2缺陷）大鼠注射了与1.25μmol/kg Cys或Hcy缀合的0.5μmol/kg HgCl(2)（含有(203)Hg(2+)）。 24和28小时后，用盐水或100mg/kg DMPS或DMSA处理大鼠。 Hg(2+) 暴露后48 小时收获组织。注射盐水的TR(-)大鼠的肾和肝Hg(2+)负荷高于相应的对照组。因此，TR(-)大鼠尿液和粪便中Hg(2+)的含量低于对照组。 DMPS或DMSA治疗后，两组大鼠肾Hg(2+)含量均明显降低，尿Hg(2+)排泄增加。在肝脏中，每种螯合剂的作用似乎取决于 Hg(2+) 的施用形式。体外实验提供了直接证据表明Hg(2+) 的DMPS 和DMSA-S-缀合物是Mrp2 的底物。总体而言，这些数据支持我们的假设，即 Mrp2 参与 DMPS 和 DMSA 介导的体内 Hg(2+) 负荷的提取。
Cysteine (Cys) and homocysteine (Hcy)-S-conjugates of inorganic mercury (Hg(2+)) are transportable species of Hg(2+) that are taken up readily by proximal tubular cells. The metal chelators, 2,3-dimercaptopropane-1-sulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA), have been used successfully to extract Hg(2+) from these cells, presumably via the multidrug resistance protein (Mrp2). In the current study, we tested the hypothesis that Mrp2 is involved in the DMPS- and DMSA-mediated extraction of Hg(2+) following administration of Hg(2+) as an S-conjugate of Cys or Hcy. To test this hypothesis, control and TR(-) (Mrp2-deficient) rats were injected with 0.5 mu mol/kg HgCl(2) (containing (203)Hg(2+)) conjugated to 1.25 mu mol/kg Cys or Hcy. After 24 and 28 h, rats were treated with saline or 100 mg/kg DMPS or DMSA. Tissues were harvested 48 h after Hg(2+) exposure. The renal and hepatic burden of Hg(2+) was greater in saline-injected TR(-) rats than in corresponding controls. Accordingly, the content of Hg(2+) in the urine and feces was less in TR(-) rats than in controls. Following treatment with DMPS or DMSA, the renal content of Hg(2+) in both groups of rats was reduced significantly and the urinary excretion of Hg(2+) was increased. In liver, the effect of each chelator appeared to be dependent upon the form in which Hg(2+) was administered. In vitro experiments provide direct evidence indicating that DMPS and DMSA-S-conjugates of Hg(2+) are substrates for Mrp2. Overall, these data support our hypothesis that Mrp2 is involved in the DMPS and DMSA-mediated extraction of the body burden of Hg(2+).