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THE PATHWAY OF ARSENIC METABLISM
Citation:
Thomas, D J. THE PATHWAY OF ARSENIC METABLISM. Presented at Fifth International Conference on Health Effects of Arsenic, San Diego, CA, July 15 - 19, 2002.
Description:
The Pathway of Arsenic Methylation
David J. Thomas, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC
Understanding the metabolic processes that convert inorganic arsenic into its methylated metabolites is central to understanding the mechanistic bases of the toxicity and carcinogenicity of this metalloid. We purified a novel S-adenosyl-L-methionine: arsenic(III) methyltransferase from liver cytosol of adult male Fischer 344 rats that catalyzes transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenicals producing methylated and dimethylated arsenicals. The mRNA for this protein predicts a 369 amino acid-residue protein (molecular mass 41056 D) that contains common methyltransferase sequence motifs. Based on similarities in the sequence of the rat protein and other predicted protein sequences, this enzyme is designated as rat Cyt19. Rat Cyt19 mRNA is expressed in many rat tissues and human Cyt19 mRNA is expressed in HepG2 cells, a human hepatoma cell line that methylates arsenic. However, Cyt19 mRNA is not found in UROTsa cells, a human urothelial cell line that does not methylate arsenic. Recombinant rat Cyt19 is fully active as an arsenic methyltransferase. Human Cyt19 is a 375 amino acid-residue protein that is quite similar in sequence to rat Cyt19 and recombinant human Cyt19 is also an arsenic methyltransferase. The catalytic functions of both rat and human Cyt19 have an absolute requirement for a dithiol-containing molecule. (This abstract does not necessarily reflect EPA policy).