Multidrug resistance proteins and the renal elimination of inorganic mercury mediated by 2,3-dimercaptopropane-1-sulfonic acid and meso-2,3-dimercaptosuccinic acid
Multidrug resistance proteins and the renal elimination of inorganic mercury mediated by 2,3-dimercaptopropane-1-sulfonic acid and meso-2,3-dimercaptosuccinic acid
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DOI：
10.1124/jpet.107.130708
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发表时间：
2008-01-01
影响因子：
3.5
通讯作者：
Zalups, Rudolfs K.
中科院分区：
文献类型：
--
作者：
Bridges, Christy C.;Joshee, Lucy;Zalups, Rudolfs K.
目前对无机汞(Hg2+)中毒的治疗方法包括使用金属螯合剂，即2，3-二硫代丙烷-1-磺酸(DMPS)或Meso-2，3-二硫代琥珀酸(DMSA)。在接触任何一种螯合剂后，Hg2+都会迅速从肾脏中排出，并从尿液中排出，推测是作为DMPS或DMSA的S结合物。多药耐药蛋白2(MRP2)参与了这一过程。我们推测，MRP2介导近端肾小管上皮细胞分泌DMPS或DMSA-S结合物。为了验证这一假说，我们研究了对照组和mrp2基因缺陷的tr大鼠对Hg2+的处置情况。静脉注射大鼠。含汞-203(2+)的HgCl2浓度为0.5mU·mol/kg。24 28h后，大鼠分别注射生理盐水、二甲基苯丙磺酸或二甲基苯丙胺。HgCl2染毒后48h取材。注射生理盐水组大鼠的肝、肾Hg2+负荷明显高于对照组。而大鼠尿和粪中Hg2+排泄量明显低于对照组。DMPs显著降低了两组大鼠肾脏和肝脏中Hg2+的含量，而非DMSA，其中对照组下降幅度最大。在DMPS治疗后，尿汞和粪汞的排泄量也显著增加，而对照组的汞排泄量更大。利用内向外膜囊泡表达MRP2的实验支持了这一观察结果，证明了Hg2+的DMPS-和DMSA-S-偶合物是MRP2的可运输底物。总而言之，这些数据支持了MRP2在DMPS和DMSA介导的肾脏Hg2+清除中的作用。
Current therapies for inorganic mercury (Hg2+) intoxication include administration of a metal chelator, either 2,3-dimercaptopropane-1- sulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA). After exposure to either chelator, Hg2+ is rapidly eliminated from the kidneys and excreted in the urine, presumably as an S-conjugate of DMPS or DMSA. The multidrug resistance protein 2 (Mrp2) has been implicated in this process. We hypothesize that Mrp2 mediates the secretion of DMPS or DMSA-S-conjugates of Hg2+ from proximal tubular cells. To test this hypothesis, the disposition of Hg2+ was examined in control and Mrp2-deficient TR- rats. Rats were injected i.v. with 0.5 mu mol/kg HgCl2 containing Hg-203(2+). Twenty-four and 28 h later, rats were injected with saline, DMPS, or DMSA. Tissues were harvested 48 h after HgCl2 exposure. The renal and hepatic burden of Hg2+ in the saline-injected TR- rats was greater than that of controls. In contrast, the amount of Hg2+ excreted in urine and feces of TR- rats was less than that of controls. DMPS, but not DMSA, significantly reduced the renal and hepatic content of Hg2+ in both groups of rats, with the greatest reduction in controls. A significant increase in urinary and fecal excretion of Hg2+, which was greater in the controls, was also observed following DMPS treatment. Experiments utilizing inside-out membrane vesicles expressing MRP2 support these observations by demonstrating that DMPS- and DMSA-S-conjugates of Hg2+ are transportable substrates of MRP2. Collectively, these data support a role for Mrp2 in the DMPS- and DMSA-mediated elimination of Hg2+ from the kidney.