Department of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Metallomics. 2011 Oct;3(10):1064-73. doi: 10.1039/c1mt00036e. Epub 2011 Jul 22.
Three minor sulfur-containing arsenic metabolites: monomethylmonothioarsonic acid (MMMTA(V)), dimethylmonothioarsinic acid (DMMTA(V)), and dimethyldithioarsinic acid (DMDTA(V)) were recently found in human and animal urine after exposure to inorganic arsenic. However, it remains unclear how the thioarsenicals are formed in the body and then excreted into the urine. It is hypothesized that the generation of thioarsenicals occurs during enterohepatic circulation. To address this hypothesis, male Sprague Dawley (SD) rats and Eisai hyperbilirubinuric (EHB) rats (with deficiency of multidrug resistance-associated protein 2) were orally administered a single dose of inorganic arsenite (iAs(III)) at 3.0 mg kg(-1) of body weight. Five hours after dosing, less than 1.0% of the dose was recovered in the bile of EHB rats, while more than 27% of the dose was recovered in the bile of SD rats, with the majority being monomethylarsinodiglutathione [MMA(SG)(2)] with a small amount of arsenic triglutathione [iAs(SG)(3)]. During the early time periods (3 h and 6 h) the arsenic levels in the liver, red blood cells (RBCs) and plasma of EHB rats were higher than those of SD rats, and approximately 76% and 87% of the dose was recovered in the RBCs of SD and EHB rats, respectively, at day 5 after dosing. However, there were no significant differences in arsenic concentration in urine between the two types of animal. Regarding the arsenic species in the urine of both types of rat, significant levels of thiolated arsenicals MMMTA(V) and DMMTA(V) were detected in SD rat urine, however in EHB rat urine only low levels of DMMTA(V) were detected. The present result of the metabolic balance and speciation study suggests that the formation of MMMTA(V) and DMMTA(V) in rats is dependent on enterohepatic circulation. In addition, in vitro experiments indicated that arsenicals excreted from bile may be transformed by gastrointestinal microbiota into MMMTA(V) and DMMTA(V), which are then absorbed into the bloodstream and finally excreted into the urine.
一甲基单硫代砷酸（MMMTA(V)）、二甲基单硫代砷酸（DMMTA(V)）和二甲基二硫代砷酸（DMDTA(V)），在接触无机砷后，最近在人和动物尿液中被发现。然而，硫代砷在体内是如何形成并随后排泄到尿液中的仍不清楚。据推测，硫代砷的生成发生在肠肝循环中。为了验证这一假说，雄性 Sprague Dawley（SD）大鼠和 Eisai 高胆红素血症（EHB）大鼠（多药耐药相关蛋白 2 缺乏）经口给予 3.0mgkg(-1)体重的单剂量亚砷酸钠（iAs(III)）。给药后 5 小时，EHB 大鼠胆汁中回收不到 1.0%的剂量，而 SD 大鼠胆汁中回收超过 27%的剂量，主要是一甲基砷酸二谷胱甘肽[MMA(SG)(2)]，少量为砷三谷胱甘肽[iAs(SG)(3)]。在早期（3 小时和 6 小时），EHB 大鼠的肝、红细胞（RBC）和血浆中的砷含量均高于 SD 大鼠，给药后第 5 天，SD 和 EHB 大鼠的 RBC 中分别回收约 76%和 87%的剂量。然而，两种动物尿液中的砷浓度没有显著差异。关于两种类型大鼠尿液中的砷形态，在 SD 大鼠尿液中检测到显著水平的硫代砷代谢物 MMMTA(V)和 DMMTA(V)，而在 EHB 大鼠尿液中仅检测到低水平的 DMMTA(V)。本代谢平衡和形态研究结果表明，MMMTA(V)和 DMMTA(V)在大鼠中的形成依赖于肠肝循环。此外，体外实验表明，从胆汁中排泄的砷可能被胃肠道微生物群转化为 MMMTA(V)和 DMMTA(V)，然后被吸收到血液中，最终排泄到尿液中。
