Chronic Methylated Arsenic-Exposure Induces Tolerance to the Acute Cytolethality of Inorganic Arsenate in Rat Liver Cells

Summary In this study we examined the effects of chronic low‑level exposure to methylated mammalian metabolites of inor‑ ganic arsenic on tolerance to an inorganic arsenate in vitro using the normal rat liver cell line TRL 1215. Cells were exposed to monomethylarsonic acid (MMAs V ; 1.3 mM dimethylarsinic acid (DMAs V did not acquire tolerance to arsenate; however the cells became arsenic tolerant after the arsenic‑free incubation. Cellular arsenic accumulation was less in these arsenic‑tolerant cells than in passage‑matched control cells. Furthermore cellular GSH depletion and inhibition of cell membrane transporters such as multidrug resistance‑associated protein increased arsenic accumulation and decreased tolerance to the acute cytolethality of arsenate in these cells chronically exposed to methylated arsenic. These results indicate that chronic exposure to methylated arsenic compounds induces tolerance to inorganic arsen‑ ate and that the tolerance is due to the induction of the arsenic excretion pathway.