Formation of dimethylthioarsenicals in red blood cells

The bladder and skin are the primary targets for arsenic-induced carcinogenicity in mammals. Thioarsenicals dimethylmonothioarsinic (DMMTAV) and dimethyldithioarsinic (DMDTAV) acids are common urinary metabolites, the former being much more toxic than non-thiolated dimethylarsinic acid (DMAV) 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 DMAV and DMDTAV were not taken up by either type of RBCs, DMAIII and DMMTAV were taken up by both (more efficiently by rat ones), though DMMTAV was taken up slowly, and then the arsenic transformed into DMDTAV was excreted from both types of animal RBCs. On the other hand, although DMAIII taken up rapidly by rat RBCs was retained in the RBCs, that taken up by human RBCs was immediately transformed into DMMTAV 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 μM DMAIII was recovered from the incubation medium in the forms of DMAV and DMMTAV in the presence of human RBCs, but not in the presence of rat RBCs (in which the arsenic was bound to hemoglobin). Thus, DMMTAV 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 DMMTAV and then excreted again into the bloodstream.