Naranmandura Hua, Suzuki Noriyuki, Suzuki Kazuo T
Graduate School of Pharmaceutical Sciences, Chiba University, Chuo, Chiba 260-8675, Japan.
Chem Res Toxicol. 2006 Aug;19(8):1010-8. doi: 10.1021/tx060053f.
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 H(2)O(2) 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 H(2)O(2) 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.
无机砷会转化为甲基化代谢产物，在人和动物体内，大部分以二甲基砷酸的形式经尿液排出。本研究旨在探讨砷的代谢情况，并确定大鼠静脉注射亚砷酸盐（0.5毫克砷/千克体重）后肝脏和肾脏中的砷代谢产物。1小时后，在两个器官的可溶性（SUP）和不可溶性沉淀物（SED）部分中发现了相似水平的砷。两个器官中超过80%的SUP砷与高分子量（HMW）蛋白质结合。与HMW和SED蛋白质结合的砷用H₂O₂氧化，并以五价形式（砷酸盐、一甲基砷酸和二甲基砷酸）释放出来。三种砷化合物的相对比例因器官、组分（HMW和SED）和时间而异。由于砷代谢产物/中间体通过用H₂O₂氧化从蛋白质中释放出来，并以五价形式回收，且在体外只有三价而非五价砷化合物与蛋白质结合，因此推断在连续甲基化途径中与蛋白质结合的砷代谢产物是三价形式；也就是说，连续甲基化反应是同时进行还原而非逐步氧化甲基化。因此，基于目前的观察结果，提出无机砷在谷胱甘肽存在下进行连续还原甲基化，而非逐步氧化甲基化，五价砷化合物（MMA(V)和DMA(V)）作为代谢终产物而非中间体存在。我们还讨论了二甲基亚砷酸与肝脏匀浆孵育后二甲基硫代砷化合物的体外形成。
