Pharmacodynamics of S-dimethylarsino-glutathione, a putative metabolic intermediate of inorganic arsenic, in mice.
Pharmacodynamics of S-dimethylarsino-glutathione, a putative metabolic intermediate of inorganic arsenic, in mice.
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S-二甲基砷基谷胱甘肽（一种假定的无机砷代谢中间体）在小鼠体内的药效学。
DOI：
10.1016/j.bcp.2016.11.020
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
and Seishiro Hirano
中科院分区：
文献类型：
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作者：
Ayaka Kato;Yayoi Kobayashi;Osamu Udagawa;and Seishiro Hirano
无机砷是众所周知的致癌物质，而亚砷酸盐（iAsIII）化合物现在被认为是几种白血病的有效治疗剂，三氧化二砷已被用于治疗复发性急性早幼粒细胞白血病（APL）。然而，最近的临床试验表明，亚砷酸盐对非APL恶性肿瘤并不总是有效的。另一种砷，S-二甲基砷-谷胱甘肽（[DMAIII（GS）]），这是一个假定的代谢中间体在肝脏代谢的iAs III，显示出治疗几种类型的淋巴瘤的前景。然而，[DMAIII（GS）]的代谢尚未得到很好的研究，可能是因为[DMAIII（GS）]在谷胱甘肽浓度低的生物液体中不稳定。在本研究中，我们将[DMAIII（GS）]静脉注射到小鼠体内，并将[DMAIII（GS）]与亚砷酸钠（NaAsO 2）的组织分布和代谢动力学进行比较。我们发现，与NaAsO 2相比，[DMAIII（GS）]在肺和脑中的分布具有独特的器官偏好。此外，[DMAIII（GS）]似乎通过在给药后快速交换其谷胱甘肽部分与血清白蛋白结合，为[DMAIII（GS）]在血浆中的更长保留时间提供了新的见解。
Inorganic arsenicals are well-known carcinogens, whereas arsenite (iAsIII) compounds are now recognized as potent therapeutic agents for several leukemias, and arsenic trioxide has been used for the treatment of recurrent acute promyelocytic leukemia (APL). However, recent clinical trials revealed that arsenite is not always effective for non-APL malignancies. Another arsenical, S-dimethylarsino-glutathione ([DMAIII(GS)]), which is a putative metabolic intermediate in the hepatic metabolism of iAsIII, shows promise for treating several types of lymphoma. However, the metabolism of [DMAIII(GS)] has not been well investigated, probably because [DMAIII(GS)] is not stable in biological fluids where the concentration of glutathione is low. In the present study, we injected [DMAIII(GS)] intravenously into mice and compared the tissue distribution and metabolic dynamics of [DMAIII(GS)] with those of sodium arsenite (NaAsO2). We found a unique organ preference for the distribution of [DMAIII(GS)] to the lung and brain in comparison to NaAsO2. Furthermore, [DMAIII(GS)] appeared to bind to serum albumin by exchanging its glutathione moiety quickly after administration, providing novel insights into the longer retention of [DMAIII(GS)] in plasma.