Formation of dimethylthioarsenicals in red blood cells.

The bladder and skin are the primary targets for arsenic-induced carcinogenicity in mammals. Thioarsenicals dimethylmonothioarsinic (DMMTA(V)) and dimethyldithioarsinic (DMDTA(V)) acids are common urinary metabolites, the former being much more toxic than non-thiolated dimethylarsinic acid (DMA(V)) and comparable to dimethylarsinous acid (DMAIII) in epidermoid cells, suggesting that the metabolic production of thioarsenicals may be a risk factor for the development of cancer in these organs. To reveal their production sites (tissues/body fluids), we examined the uptake and transformation of the four dimethylated arsenicals by incubation with rat and human red blood cells (RBCs). Although DMA(V) and DMDTA(V) were not taken up by either type of RBCs, DMAIII and DMMTA(V) were taken up by both (more efficiently by rat ones), though DMMTA(V) was taken up slowly, and then the arsenic transformed into DMDTA(V) was excreted from both types of animal RBCs. On the other hand, although DMA(III) taken up rapidly by rat RBCs was retained in the RBCs, that taken up by human RBCs was immediately transformed into DMMTA(V) and then excreted into the incubation medium without being retained in the RBCs. In a separate experiment, arsenic remaining in primary rat hepatocytes after incubation with 1.5 microM DMAIII was recovered from the incubation medium in the forms of DMA(V) and DMMTA(V) in the presence of human RBCs, but not in the presence of rat RBCs (in which the arsenic was bound to hemoglobin). Thus, DMMTA(V) was detected in the medium only in the presence of human RBCs and increased with incubation time. It was proposed that arsenic is excreted from hepatocytes into the bloodstream in the form of DMAIII and then taken up by RBCs in humans, where it is transformed into DMMTA(V) and then excreted again into the bloodstream.