Studies on the Mechanisms of Arsenic Tolerance Induced in Rat Liver Cells by Chronic Exposure to Methylated Arsenicals

Abstract

In this study, we examined the effects of chronic low-level exposure to methylated arsenicals on tolerance to inorganic arsenite in vitro using the normal rat liver cell line TRL 1215. For 20 weeks, cells were exposed to methylated mammalian metabolites of inorganic arsenicals; monomethylarsonic acid (MMAs^v; 1.3 mM), dimethylarsinic acid (DMAs^v; 700 μM) or trimethylarsine oxide (TMAs^vO; 10 mM). These cells acquired tolerance to the acute cytolethality of inorganic arsenite. Cellular arsenic accumulation was less in chronic methylated arsenical-exposed cells than passage-matched control cells. Long-term exposure to methylated arsenicals increased cellular glutathione S-transferase (GST) activity and cellular reduced glutathione (GSH) levels, although only chronic exposure to DMAs^v significantly decreased cellular GSH levels. Cellular GSH depletion increased arsenic accumulation and decreased tolerance to the acute cytolethality of arsenite in these chronic methylated arsenical-exposed cells. These results indicate that chronic exposure to methylated arsenicals induces tolerance to inorganic arsenite, and that cellular GSH may play an important role in the induction of this tolerance.