Selenium Compounds Modulate the Activity of Recombinant Rat AsIII-Methyltransferase and the Methylation of Arsenite by Rat and Human Hepatocytes

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Abstract
Formation of methylated metabolites is a critical step in the metabolism of inorganic arsenic or selenium. We have previously shown that under conditions of a concurrent exposure sodium selenite inhibits methylation of arsenite by cultured rat hepatocytes. Here, we compare the effects of sodium selenite and mono-, di-, and trimethylated selenium compounds on the methylation of arsenite by purified recombinant rat AsIII-methyltransferase (Cyt19) and by primary rat and human hepatocytes. Among these compounds, sodium selenite was the most potent inhibitor of the methylation of arsenite by the recombinant enzyme (Ki = 1.4 μM) and by cultured cells. In both systems, methylseleninic acid was an order of magnitude less potent an inhibitor (Ki = 19.4 μM) than was sodium selenite. Dimethylselenoxide and trimethylselenonium iodide were weak activators of recombinant AsIII-methyltransferase activity but were weak inhibitors of arsenite methylation in hepatocytes. These data suggest that selenite, rather than its methylated metabolites, is responsible for inhibition of arsenite methylation in cultured hepatocytes and that inhibition may involve direct interactions between selenite and AsIII-methyltransferase.