Generation of thioarsenicals is dependent on the enterohepatic circulation in rats

Abstract

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.

Proposal for novel metabolic pathway of highly toxic dimethylated arsenics accompanied by enzymatic sulfuration, desulfuration and oxidation

“…With regard to the metabolic production of thioarsenicals, hydrogen sulfide produced by anaerobic flora could directly convert DMA V and trimethylarsine oxide to dimethylated and trimethylated thioarsenicals, respectively, via chemical processes [27]. Only one study concerning transformation of DMMTA V from arsenite with a possible involvement of intestinal bacteria flora has been reported so far [28]. However, several have reported on the metabolic production of DMMTA V in liver and blood.…”

Toxicological properties of the thiolated inorganic arsenic and arsenosugar metabolite thio-dimethylarsinic acid in human bladder cells

“…Where in the human body and how thio-DMA V is formed is still unknown [9][10][11]. It might be generated from oxyarsenicals by the exchange of an O atom by an S atom, e.g.…”

Speciation, Metabolism, Toxicity, and Protein-binding of Different Arsenic Species in Human Cells

“…7 Interestingly, while in general trivalent arsenic compounds are more toxic than their pentavalent counterparts, dimethylmonothioarsinic acid (DMMTA V ) has been shown to be unusually highly toxic for a pentavalent species. [10][11][12][13] According to Watanabe 14,15 While the toxicity of DMMTA V was found to be similar to the even more toxic dimethylarsinous acid (DMA III ) in epidermoid carcinoma cells, in human lung adenocarcinoma epithelium cells it was found to be less cytotoxic than dimethylarsino glutathione (DMA III (GS)). 13,16 Compared to dimethylarsinic acid (DMA V ), the corresponding non-thiolated pentavalent species, DMMTA V was found to be about 10-fold more cytotoxic in HepG2 cells derived from human hepatocarcinoma and approximately 80 times more toxic in epidermoid cells.…”

“…Interestingly, while in general trivalent arsenic compounds are more toxic than their pentavalent counterparts, DMMTA V has been shown to be unusually highly toxic for a pentavalent species. [10][11][12][13]98 Consequently, it was very important to understand and evaluate the toxicity of these species and to measure the ability of cells to take them up. glutathione persulfide as a model for protein persulfides.…”

“…10,11,14,25,35,36,114,155 Interestingly, while in general trivalent arsenic compounds are more toxic than their pentavalent counterparts, DMMTA V has been shown to be unusually highly toxic for a pentavalent species. [10][11][12][13]98 According compounds cannot be accurately estimated. 158,159 In red blood cells it was proposed that the source of sulfur may be sulfane sulfur.…”