Trivalent arsenicals are bound to proteins during reductive methylation
Trivalent arsenicals are bound to proteins during reductive methylation
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DOI：
10.1021/tx060053f
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发表时间：
2006-08-21
影响因子：
4.1
通讯作者：
Suzuki, Kazuo T.
中科院分区：
文献类型：
--
作者：
Naranmandura, Hua;Suzuki, Noriyuki;Suzuki, Kazuo T.
无机砷转化为甲基化代谢物，在人类和动物中大部分以二甲基胂酸的形式随尿排出。本研究旨在探讨砷的代谢，并确定砷的肝和肾代谢产物后，静脉注射亚砷酸盐（0.5毫克砷/公斤体重）在大鼠。相似水平的砷被发现在可溶性（sodium）和不溶性沉积物（SED）部分的两个器官后1小时。超过80%的砷结合到高分子量（HMW）蛋白质在这两个器官。与HMW和SED蛋白结合的砷被H2 O2氧化，并以五价形式（砷酸盐、单甲基胂酸和二甲基胂酸）释放。三种砷的相对比例根据器官、组分（HMW和SED）和时间而变化。由于砷代谢物/中间体通过H2 O2氧化从蛋白质中释放出来，并以五价形式回收，并且在体外只有三价砷而不是五价砷与蛋白质结合，因此推断在连续甲基化途径中与蛋白质结合的砷代谢物为三价形式;也就是说，连续的甲基化反应发生同时的还原甲基化而不是逐步的氧化甲基化。因此，根据目前的观察结果，有人提出，无机砷是连续甲基化还原谷胱甘肽的存在下，而不是逐步氧化甲基化，五价砷（MMA（V）和DMA（V））作为代谢的最终产物，而不是中间体。我们还讨论了二甲基亚胂酸与肝匀浆孵育后二甲基硫代砷的体外形成。
Inorganic arsenic is converted to methylated metabolites, and most is excreted in urine as dimethylarsinic acid in humans and animals. The present study was conducted to investigate the metabolism of arsenic and identify hepatic and renal metabolites of arsenic after an intravenous injection of arsenite (0.5 mg As/kg body weight) in rats. Similar levels of arsenic were found in the soluble (SUP) and nonsoluble sediment (SED) fractions of both organs after 1 h. More than 80% of the SUP arsenic was bound to high molecular weight (HMW) proteins in both organs. Arsenic bound to the HMW and SED proteins were oxidized with H2O2 and released in the pentavalent forms (arsenate, monomethylarsonic, and dimethylarsinic acids). The relative ratios of the three arsenicals changed depending on organ, fraction (HMW and SED), and time. Since the arsenic metabolites/intermediates were liberated from proteins by oxidation with H2O2 and recovered in the pentavalent forms, and only tri- but not pentavalent arsenicals were bound to proteins in vitro, it was deduced that arsenic metabolites bound to proteins during the successive methylation pathway are in the trivalent forms; that is, successive methylation reaction takes place with simultaneous reductive rather than stepwise oxidative methylation. Thus, on the basis of the present observations, it was proposed that inorganic arsenic was successively methylated reductively in the presence of glutathione, rather than a stepwise oxidative methylation, and pentavalent arsenicals (MMA(V) and DMA(V)) were present as end products of metabolism, rather than intermediates. We also discussed the in vitro formation of dimethylthioarsenicals after incubating dimethylarsinous acid with liver homogenate.