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MINIREVIEW

Arsenic (+3 Oxidation State) Methyltransferase and the Methylation of Arsenicals

David J. Thomas^*,1, Jiaxin Li, Stephen B. Waters, Weibing Xing, Blakely M. Adair^*, Zuzana Drobna, Vicenta Devesa^,2 and Miroslav Styblo^,

^* Pharmacokinetics Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Department of Nutrition, Schools of Public Health and of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

To whom requests for reprints should be addressed at ¹ Pharmacokinetics Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711. E-mail: thomas.david{at}epa.gov

Metabolic conversion of inorganic arsenic into methylated products is a multistep process that yields mono-, di-, and trimethylated arsenicals. In recent years, it has become apparent that formation of methylated metabolites of inorganic arsenic is not necessarily a detoxification process. Intermediates and products formed in this pathway may be more reactive and toxic than inorganic arsenic. Like all metabolic pathways, understanding the pathway for arsenic methylation involves identification of each individual step in the process and the characterization of the molecules which participate in each step. Among several arsenic methyltransferases that have been identified, arsenic (+3 oxidation state) methyltransferase is the one best characterized at the genetic and functional levels. This review focuses on phylogenetic relationships in the deuterostomal lineage for this enzyme and on the relation between genotype for arsenic (+3 oxidation state) methyltransferase and phenotype for conversion of inorganic arsenic to methylated metabolites. Two conceptual models for function of arsenic (+3 oxidation state) methyltransferase which posit different roles for cellular reductants in the conversion of inorganic arsenic to methylated metabolites are compared. Although each model accurately represents some aspects of enzyme’s role in the pathway for arsenic methylation, neither model is a fully satisfactory representation of all the steps in this metabolic pathway. Additional information on the structure and function of the enzyme will be needed to develop a more comprehensive model for this pathway.

Key Words: arsenic • methylation • arsenic (+3 oxidation state) methyltransferase

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