Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Chemosphere. 2010 Sep;81(2):206-13. doi: 10.1016/j.chemosphere.2010.06.043. Epub 2010 Jul 1.
Quite a few new thioarsenicals have recently been found in urine of arsenic-exposed humans and animals, and some of them have been shown to be highly toxic to cells. However, little is known about their toxic effects and metabolism in the body. In order to elucidate the toxic mechanism of thioarsenicals, we further focused on the distribution and metabolism of monomethylmonothioarsonic acid (MMMTA(V)) in rats. MMMTA(V) was synthesized chemically and injected intravenously into rats at the dose of 0.5mg As/kg, followed by speciation analysis of selected organs and body fluids at 10 min and 12h after the injection. MMMTA(V) was excreted into urine in its intact form, and approximately 35% of the dose was recovered in urine at 12h after the injection, suggesting that MMMTA(V) was taken up more effectively by organs/tissues than non-thiolated, monomethylarsonous acid (MMA(V)) previously studied. On the other hand, the liver and kidneys contained arsenic that was in a protein-binding form with free forms of DMA(V) or DMDTA(V) at 10 min, and disappeared at 12h after the injection. Moreover, these bound arsenic species in kidneys were converted back to MMA(V) after oxidation with H(2)O(2), suggesting that the arsenic bound to proteins had been reduced within the body and was in a trivalent oxidation state. In red blood cells (RBCs), most of the arsenic was in the form of DMA(III) bound to hemoglobin (Hb), and approximately 40% of the dose was recovered in RBCs at 12h after injection. These results indicate that arsenic accumulated preferentially in RBCs after being transformed to DMA(III). In addition, we have also discussed the effect of MMMTA(V) on viability of human bladder cancer T24 cells in comparison with MMA(V). Consequently, MMMTA(V) was assumed to be a more toxic arsenic metabolite than non-thiolated MMA(V).
最近在暴露于砷的人类和动物的尿液中发现了相当数量的新型硫代砷，其中一些已被证明对细胞具有高度毒性。然而，对于它们在体内的毒性作用和代谢知之甚少。为了阐明硫代砷的毒性机制，我们进一步关注一甲基单硫代砷酸（MMMTA（V））在大鼠体内的分布和代谢。通过化学合成制备 MMMTA（V），并以 0.5mg As/kg 的剂量静脉注射到大鼠体内，然后在注射后 10min 和 12h 对选定器官和体液进行形态分析。MMMTA（V）以其完整形式排泄到尿液中，并且在注射后 12h 从尿液中回收约 35%的剂量，这表明 MMMTA（V）比以前研究的非硫代、一甲基砷酸（MMA（V））更有效地被器官/组织吸收。另一方面，肝脏和肾脏在 10min 时含有与游离的 DMA（V）或 DMDTA（V）形成蛋白结合的砷，并且在注射后 12h 时消失。此外，在用 H（2）O（2）氧化后，肾脏中这些结合的砷物种被转化回 MMA（V），这表明与蛋白质结合的砷在体内已被还原，并处于三价氧化态。在红细胞（RBCs）中，大部分砷以与血红蛋白（Hb）结合的 DMA（III）形式存在，并且在注射后 12h 从 RBCs 中回收约 40%的剂量。这些结果表明，砷在转化为 DMA（III）后优先在 RBCs 中积累。此外，我们还比较了 MMMTA（V）与 MMA（V）对人膀胱癌 T24 细胞活力的影响。因此，与非硫代 MMA（V）相比，MMMTA（V）被认为是一种更具毒性的砷代谢物。
