Distributions and chemical forms of arsenic after intravenous administration of dimethylarsinic and monomethylarsonic acids to rats.

The observed toxicity of arsenic is highly dependent on animal species and differences in metabolism. Rats are one of the most tolerant species, and the metabolic pathway is quite different in some aspects from those of other mammals. The distinct metabolic pathway including the preferential accumulation in red blood cells (RBCs) has been explained, whereby allowing an effective use of rats as an animal model for the arsenic metabolism. In the present study, distributions of arsenic among organs/tissues/body fluids and their chemical forms were studied after intravenous injection of arsenic in the forms of dimethylarsinic (DMA(V)) and monomethylarsonic acids (MMA(V)) to rats. DMA(V) and MMA(V) were mostly excreted into urine immediately after the injection as the intact forms, and both forms were taken up less effectively by organs/tissues than arsenite. The methylated arsenics distributed in organs/tissues were excreted directly into urine and excreted before being redistributed in RBCs. DMA(V) and MMA(V) taken up by the liver were transformed to metabolites not yet identified, accumulated transiently in the liver, and then they disappeared from the liver. The unidentified metabolites were assumed to be transformed from dimethylarsinic acid (DMA(III)) following the consecutive metabolic reactions [MMA(V) --> monomethylarsonous acid (MMA(III)) --> DMA(V) --> DMA(III)]. The unidentified metabolites were excreted not into the bile but into the bloodstream. Injections of DMA(V) and MMA(V) induced a biliary excretion of arsenic but only at 0.2-0.3% of the dose, the arsenic in the bile being their intact free forms.

Dimethylthioarsenicals as arsenic metabolites and their chemical preparations.

Two unidentified arsenic metabolites were detected in the liver of rats on a gel filtration column by HPLC inductively coupled argon plasma mass spectrometry after an injection of dimethylarsinic (DMA(V)), dimethylarsinous (DMA(III)), monomethylarsonic (MMA(V)), or monomethylarsonous (MMA(III)) acid. The same arsenicals were also produced in vitro by incubation of DMA(III) in the liver supernatant but not by DMA(V). The two arsenic metabolites eluted at the same retention times as those of the two arsenicals prepared by reaction of DMA(V) with either thiosulfate plus disulfite or hydrogen sulfide or sodium sulfide plus sulfuric acid. The faster and slower eluting products on a gel filtration column were assigned as dimethyldithioarsinic acid (dimethylarsinodithioic acid) (DMTA(V)) and dimethylthioarsinous acid (DMTA(III)) from mass spectrometric data at m/z = 170 and 138 by electrospray ionization mass spectrometry with negative and positive ion modes, respectively. They were prepared selectively by reacting DMA(V) with hydrogen sulfide or sodium sulfide plus sulfuric acid under different reaction conditions. DMA(III) but not DMA(V) was transformed to DMTA(III) and DMTA(V) in the presence of sodium sulfide in vitro, suggesting that DMA(V) is reduced to DMA(III) with hydrogen sulfide, thiolated to DMTA(III), and then further thiolated oxidatively to DMTA(V). Metabolically, it is assumed that DMA(III) is transformed to DMTA(III) in the presence of sulfide ions, and then, DMTA(III) is oxidatively thiolated to DMTA(V). As the chemical species produced by reduction with the Reay and Asher method are DMTA(III) and DMTA(V), and different from DMA(III), the studies carried out with DMA(III) with the Reay and Asher method have to be reexamined.