Active arsenic species produced by GSH-dependent reduction of dimethylarsinic acid cause micronuclei formation in peripheral reticulocytes of mice

Dimethylarsine and trivalent dimethylated arsenic, metabolites of inorganic arsenics, have received considerable attention in current research because of their biological activities. We attempted to determine the appearance of micronucleated reticulocytes (MNRETs) in mouse peripheral blood following intraperitoneal administration of dimethylarsinous iodide (DMI) and trimethylarsine (TMA), model compounds of trivalent dimethylated arsenic and dimethylarsine, respectively. A significant increase in the number of MNRETs was observed with TMA, but not with DMI. Furthermore, MNRETs only appeared with 10.6 mg/kg of dimethylarsinic acid (DMA) following its co-injection with reduced glutathione (GSH). These results suggest that micronucleus formation may need further metabolic reduction of trivalent dimethylated arsenic, i.e. the production of dimethylarsine, by an excess amount of GSH. Meanwhile, the increase in MNRETs by administration of arsenite at 7.6 mg/kg, an equivalent dose to DMA as As, was remarkably diminished by co-administration with GSH. These results indicate that GSH plays an important role in the genotoxic process of arsenics, particularly by dimethylated arsenic.