Reaction mechanism underlying the in vitro transformation of thioarsenicals
Reaction mechanism underlying the in vitro transformation of thioarsenicals
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DOI：
10.1016/j.taap.2008.05.005
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发表时间：
2008-09-15
影响因子：
3.8
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.
由于砷的毒性，一些硫代砷化合物具有很高的毒性，并且普遍存在于哺乳动物的尿液中，因此引起了人们的广泛关注。我们以前报道过，硫代砷化合物可能是在红细胞(RBC)中产生的。在这里，我们用S-34标记的二甲基硫代阿司匹酸(S-34-DMMTA(V))和纯化的脂肪血红蛋白(Hb)或大鼠红细胞裂解物进一步研究了红细胞中硫代砷化合物的产生和代谢的机制。S-34-DMMTA(V)与纯化的脂肪Hb孵育后不与Hb结合，保持其原有的形式。然而，当S-34-DMMTA(V)与大鼠红细胞裂解液孵育时，只检测到与Hb(As-Hb)结合的砷，而不是硫(S-34)。此外，还检测到另一种含硫的砷产物(S-34)，其摩尔比为S-34/砷=2，被鉴定为二甲基二硫代精氨酸(DMDTA(V))，表明砷不以S-34-二甲基亚氨基甲酸(V)的形式与Hb结合，而以二甲基砷酸(DMA(III))的形式结合。也就是说，DMMTA(V)似乎被水解成二甲基砷酸(DMA(V))和(HS-)-S-34，释放出来的(HS-)-S-34与DMMTA(V)反应生成DMDTA(V)。因此，DMMTA(V)被转化为DMDTA(V)和DMA(V)(2DMMTA(V)->；DMDTA(V)+DMA(V))，后者在GSH存在下被还原为DMA(III)并与Hb结合。在另一项实验中，S-34-DMMTA(V)与硫化物(Na2S)和谷胱甘肽(GSH)孵育。仅在Na2S或GSH存在下，DMMTA(V)不能转化为DMDTA(V)，但在Na2S和GSH共同存在下，DMMTA(V)可转化为DMDTA(V)。我们的结果表明，DMMTA(V)在酶作用下被分解为DMA(V)和硫化物，前者被还原为DMA(III)并与Hb结合，后者与DMMTA(V)反应生成DMDTA(V)。因此，DMMTA(V)以类似于歧化反应的方式通过水解反应转化为DMDTA(V)和DMA(V)，DMA(V)被还原并与HB(AS-HB)结合，并且在介质中存在硫化物的情况下更多地生成DMDTA(V)。(C)2008 Elsevier Inc.保留所有权利。
Thioarsenicals have been paid much attention due to the toxicity of arsenic, since some of them are highly toxic and commonly found in the urine of mammals. We previously reported that thioarsenicals might be produced in red blood cells (RBCs). Here, we further characterized the mechanism underlying the production and metabolism of thioarsenicals in RBCs using S-34-labeled dimethylmonothioarsinic acid (S-34-DMMTA(v)) and purified Fat hemoglobin (Hb) Ora rat RBC lysate. S-34-DMMTA(v) did not bind to Hb on incubation with purified Fat Hb, remaining in its original form. However, when S-34-DMMTA(v) was incubated with a rat RBC lysate, only arsenic, i.e., not sulfur (S-34), was detected in a form bound to Hb (As-Hb). In addition, another arsenic product containing sulfur (S-34) in the molar ratio of S-34/As=2 was detected, which was assigned as dimethyldithioarsinic acid (DMDTA(v)), suggesting that arsenic does not bind to Hb in the form of S-34-DMMTA(v) but does so in the form of dimethylarsinous acid (DMA(III)). Namely, DMMTA(v) appeared to be hydrolyzed into dimethylarsinic acid (DMA(v)) and (HS-)-S-34, and the released (HS-)-S-34 reacted with DMMTA(v) to produce DMDTA(v). Thus, DMMTA(v) was transformed into DMDTA(v) and DMA(v) (2DMMTA(v) - >DMDTA(v)+DMA(v)), the latter product being reduced to DMA(III) in the presence of GSH and bound to Hb. In a separate experiment, S-34-DMMTA(v) was incubated with Sulfide (Na2S) and GSH. Although DMMTA(v) was not transformed into DMDTA(v) in the presence of only Na2S or GSH, it was transformed into DMDTA(v) in the presence of both Na2S and GSH. Our results suggest that DMMTA(v) is hydrolyzed enzymatically into DMA(v) and sulfide, the former being reduced to DMA(III) and bound to Hb, and the latter reacting with DMMTA(v) to yield DMDTA(v). Thus, DMMTA(v) is transformed into DMDTA(v) and DMA(v) through a hydrolytic reaction in a manner similar to a disproportionation reaction, DMA(v) being reduced and bound to Hb (As-Hb), and DMDTA(v) being produced more in the presence of sulfides in the medium. (C) 2008 Elsevier Inc. All rights reserved.