5. Metabolism
In general, arsenic is metabolised via reduction, glutathione (GSH) conjugation and subsequent methylation in mammals [38]. There are major differences among species. For instance, the chimpanzee and the marmoset monkey were found not to methylate arsenicals 39 and 40. In man, monomethylarsonic acid (MMA) is less quantitatively metabolized to DMA than in other mammals (10–20% MMA versus a few percent MMA of the total arsenic appearing in urine) 41 and 42. However, there is evidence for the existence of an arsenic methylation polymorphism. Andean women residing in a region with elevated exposure to environmental arsenic were found to excrete only 2% of the total arsenic in urine as MMA [43]. Arsenic methylation takes place mainly in the liver [35]. In contrast to fibroblast cell lines 32 and 44primary hepatocytes in culture show a high methylation capacity [29]. Methylation is considered a very effective step in arsenic detoxification [45]. However, it has to be noted that in vitro As(III) will not be detoxified by methylation as effectively as in vivo.
In contrast to arsenic, quantities of antimony changing valency after incorporation seem to be small, i.e. approximately 5–10%. In man as well as in rodents, only a few percent of pentavalent antimony were reduced to the trivalent form 46, 47 and 48. Furthermore, Sb(III) after application seems to be oxidized to Sb(V) in similar quantities. Evidence of antimony methylation in mammals is low. Thus, it seems that Sb(III) is not as effectively detoxified in the body as arsenic. Although not methylated itself, SbCl3 inhibited the methylation of arsenic in vitro 49 and 50. These observations might have an important impact on toxicological risk assessment of trivalent antimonials. There is evidence indicating that Sb(III) is conjugated to GSH and excreted via the bile undergoing an enterohepatic cycle in the rat [50]. In that study it seemed that antimony and GSH did not form a stable bond and hydrolysed with a following reabsorption of antimony. The vicinal dithiol 2,3-dimercaptosuccinic acid worked well as an antidote against acute intoxication with antimonyl(III) tartrate. In contrast, GSH was not effective [51]. This result could further confirm the chemical instability of an antimony–GSH complex.
The fact that arsenic causes DNA–protein crosslinks [52]and that it is metabolised by glutathione conjugation underlines its high affinity to thiol groups. In fact, As(III) reacts with GSH to form As(GS)3[53]. Moreover, the affinity of As(III) to vicinal dithiols was higher than it was for GSH 51 and 54. Despite high levels of glutathione in the cytosol, the in vivo binding of trivalent arsenic to specific cytosolic proteins was not prevented [55]. Furthermore, trivalent arsenic has been used in affinity chromatography as a probe for dithiol proteins [56]. In contrast, the affinity of antimony to thiol residues and its potency to provoke DNA–protein crosslinks seems to be far lower than it is for arsenic.