The role of glutathione in the metabolism of diphenylarsinic acid in rats
The role of glutathione in the metabolism of diphenylarsinic acid in rats
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DOI：
10.1039/c2mt20228j
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发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
Hirano, Seishiro
中科院分区：
文献类型：
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作者：
Kobayashi, Yayoi;Hirano, Seishiro
二苯胂酸（DPAA(V)）是一种化学前体，也是Clark 1（氯化二苯胂）和Clark 2（氰化二苯胂）等含砷化学武器的降解产物。与无机砷相比，DPAA(V) 的毒理学研究结果有限。为了阐明DPAA(V)的毒性机制，我们研究了DPAA(V)在体内的代谢行为。具体而言，我们研究了口服DPAA(V)剂量为1.0 mg As kg(-1)体重的大鼠中DPAA(V)及其代谢物的分布和胆汁排泄。通过 HPLC-ICP-MS 和 HPLC-ESI-MS 测定，DPAA(V) 以原始 DPAA(V) 或 DPAA-GSH 复合物 (DPAG(III)) 形式排泄到胆汁中，其中 DPAG(III) 是主要化学形式。给药后三小时和三天，红细胞中分别积累了约 1.7% 和 2.4% 的剂量。三天内大约91%的剂量以DPAA(V)的形式从尿液和粪便中排出，其中大部分通过尿液排出。通过将 DPAA(V) 或 DPAG(III) 与大鼠红细胞悬浮液（10% Tris-HCl 缓冲盐水）一起孵育（37 摄氏度下长达 3 小时），体外研究了红细胞中砷的积累。约80%的DPAG(III)剂量在三十秒内被红细胞吸收，而约35%的DPAA(V)剂量在孵育三小时后被红细胞吸收。 DPAG(III) 可能被水解并转化为三价非结合砷（二苯胂酸，DPA(III)），它也在红细胞中积累。正如预期的那样，DPA(III) 对红细胞蛋白的亲和力比 DPAA(V) 更高。
Diphenylarsinic acid (DPAA(V)) is a chemical precursor as well as a degradation product of arsenic-containing chemical weapons such as Clark 1 (diphenylarsine chloride) and Clark 2 (diphenylarsine cyanide). Compared to inorganic arsenicals, toxicological findings on DPAA(V) are limited. To elucidate the mechanism of DPAA(V) toxicity, we investigated the metabolic behavior of DPAA(V) in the body. Specifically, we examined the distribution and biliary excretion of DPAA(V) and its metabolites in rats orally administered DPAA(V) at a dose of 1.0 mg As kg(-1) body weight. DPAA(V) was excreted in bile, either as the original DPAA(V) or as a DPAA-GSH complex (DPAG(III)), as determined by HPLC-ICP-MS and HPLC-ESI-MS, with DPAG(III) being the main chemical form. Approximately 1.7% and 2.4% of the dose was accumulated in erythrocytes three hours and three days after administration, respectively. Approximately 91% of the dose was excreted in urine and feces as DPAA(V) in three days, mostly in the urine. Accumulation of arsenic in erythrocytes was investigated in vitro by incubating (at 37 degrees C for up to three hours) DPAA(V) or DPAG(III) with a suspension of rat erythrocytes (10% in Tris-HCl-buffered saline). Approximately 80% of the DPAG(III) dose was taken up by erythrocytes within thirty seconds, while approximately 35% of the DPAA(V) dose was taken up by erythrocytes after three hours of incubation. DPAG(III) was possibly hydrolyzed and converted to trivalent unconjugated arsenical (diphenylarsinous acid, DPA(III)), which also was accumulated in erythrocytes. As expected, DPA(III) exhibited greater affinity for erythrocyte proteins than did DPAA(V).