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RECOMBINANT RAT CYT19, AN ARSENIC METHYLTRANSFERASE, EFFICIENTLY GENERATES TRIMETHYLARSINE OXIDE IN THE ABSENCE OF GLUTATHIONE
Citation:
Waters, S. B., V. Devesa, Z. Drobna, M Styblo, AND D J. Thomas. RECOMBINANT RAT CYT19, AN ARSENIC METHYLTRANSFERASE, EFFICIENTLY GENERATES TRIMETHYLARSINE OXIDE IN THE ABSENCE OF GLUTATHIONE. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Chronic exposure to inorganic arsenic (iAs), a toxic metalloid sometimes present in drinking water, is associated with increased prevalences of various cancers and other disorders. Humans and many other species enzymatically convert iAs into methylated metabolites. The major metabolites are mono- and dimethylated arsenicals; however, trimethylated arsenicals have been detected in urine and expired breath following exposure to iAs. The As methyltransferase of rat liver is encoded by the cyt19 gene that produces cyt19, a 42kDa cytosolic protein. Recombinant rat cyt19 (rrcyt19) has been used to study the enzymology of As methylation. Mono- and dimethylated arsenicals generated in assays with rrcyt19 are usually resolved by thin layer chromatography using an acetone:water:acetate (3:1:1) solvent system. However, chromatography with an isopropanol:water:acetate (10:2.5:1) solvent system revealed an unidentified metabolite. This species comigrated with authentic trimethylarsine oxide (TMAO). This metabolite had identical properties with authentic TMAO when analyzed by hydride generation-atomic absorption spectrometry and was identified as TMAO by ICP-mass spectrometric analysis. Addition of glutathione (GSH) to reactions containing iAs and rrcyt19 increased the rate of formation of methylated and dimethylated arsenicals but suppressed formation of TMAO. Addition of GSH to reactions containing iAs and rrcyt19 also reduced the loss of a volatile arsenical that may be trimethlyarsine (TMA). Although TMAO is a not a toxic methylated arsenical, TMA has recently been shown as a potent DNA-damaging compound. Thus, generation of TMA in cyt19-catalyzed reactions may be a pathway for metabolic activation of iAs. (This abstract does not necessarily reflect U.S. EPA policy.)