Dimethylthioarsenicals as Arsenic Metabolites and Their Chemical Preparations

Abstract

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.

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration

“…Regarding the detection of DMA(III) in urine, it has recently been reported that DMA(III) has been mistaken for a sulfur-containing dimethylarsenic compound (Hansen et al, 2004;Suzuki et al, 2004aSuzuki et al, , 2004b. These results were based on mass spectral analysis of several products formed from DMA(V) by reacting it directly with sulfur-containing compounds under acidic conditions.…”

“…In contrast, monomethylarsonous acid (MMA(III)) (trivalent monomethylarsenic) was readily methylated in vitro to dimethylarsenic (Styblo et al, , 1999. Recent studies with trivalent monomethylarsenic, formed by reacting MMA(V) with thiols, and administered po (0.1-0.5 mg/ kg) or iv (0.5 mg/kg) (Suzuki et al, 2004b) to rats showed that it was methylated to DMA(V). The low rate of conversion of MMA(V) is surprising, given the relative rapidity of iAs methylation by many species.…”

Commonalities in Metabolism of Arsenicals

“…For instance, arsinothioyls confound identification by HPLC, pH-selective HG-ICP-MS, or anionexchange chromatography. [35,36] Formation in vitro or in vivo of thioylated metabolites by rat liver [37,38] may require enzymatic generation of hydrogen sulfide. [39] Understanding formation of arsinothioyls and their biological activities will provide more information about roles of metabolism in the actions of arsenicals as toxins and carcinogens.…”

Development of mass spectrometric methods for detecting arsenic-glutathione complexes

“…. The predominant forms of arsenic in drinking water are arsenite and arsenate (iAs III and iAs", respectively), the inorganic species which are regarded as human carcinogens [2,3]. Inorganic arsenic compounds are transformed in the body by repetitive reduction and oxidative methylation reactions, leading to the formation of organoarsenic species, the major of which are monomethylarsonic acid (MMAv) and dimethylarsinic acid (DMAV) [3,4].…”

“…The predominant forms of arsenic in drinking water are arsenite and arsenate (iAs III and iAs", respectively), the inorganic species which are regarded as human carcinogens [2,3]. Inorganic arsenic compounds are transformed in the body by repetitive reduction and oxidative methylation reactions, leading to the formation of organoarsenic species, the major of which are monomethylarsonic acid (MMAv) and dimethylarsinic acid (DMAV) [3,4].The precise pathway through which inorganic arsenic is metabolized in the organism is not yet known in sufficient detail. The generally accepted methylation mechanism involves the initial conversion of pentavalent arsenic species iAsv to trivalent species iAs IlI through a two-electron reduction, while oxidative addition of a methyl group follows [4,5].…”