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PRODUCTION AND BIOLOGICAL SIGNIFICANCE OF METHYLATED TRIVALENT ARSENICALS
Citation:
Styblo, M, Z. Drobna, Walton, Felecia S, I. Jaspers, S. Lin, S. B. Waters, AND D J. Thomas. PRODUCTION AND BIOLOGICAL SIGNIFICANCE OF METHYLATED TRIVALENT ARSENICALS. Presented at The Japan Society for Biomedical Research on Trace Elements, Wako, Japan, Oct. 28-Nov2, 2002.
Description:
PRODUCTION AND BIOLOGICAL SIGNIFICANCE OF METHYLATED TRIVALENT ARSENICALS
Miroslav Styblo1,2,*, Zuzana Drobna1, Felecia S. Walton1, Ilona Jaspers1,2, Shan Lin3,
Stephen B. Waters3, David J. Thomas4
1Department of Pediatrics, 2Center for Environmental Medicine and Lung Biology, 3Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
4Pharmacokinetics 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, USA
*E-mail: styblo@med.unc.edu
Methylated arsenicals that contain arsenic in the +3 oxidation state are products of the metabolism of inorganic arsenic (iAs) in humans. The metabolic pathway for iAs involves two classes of reactions: the reduction of pentavalent arsenicals to trivalency and the oxidative methylation of trivalent arsenicals that yields methylated products containing pentavalent arsenic (Scheme I). Thus, both trivalent and pentavalent arsenicals are intermediates or products of this pathway. Methylated arsenicals that contain trivalent arsenic, methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII), are, unlike their homolgues containing pentavalent arsenic, methylarsonic acid (MAsV) and dimethylarsinic acid (DMAsV), potent inhibitors of several enzymes, including glutathione reductase [1], pyruvate decarboxylase [2], and especially thioredoxin reductase [3,4]. Other adverse effects are associated with exposure to MAsIII and DMAsIII. These effects include
1. MAsIII and DMAsIII are more cytotoxic to animal and human cells than arsenite (iAsIII) [2,5],
2. MAsIII is more acutely toxic to laboratory animals than iAsIII [6],
3. MAsIII and DMAsIII induce production of growth promoting cytokines and cell proliferation in human cells [7],
4. MAsIII, and especially DMAsIII are more potent than iAsIII in damaging DNA in in vitro systems and in cultured cells [8], and
5. MAsIII and DMAsIII are more potent than iAsIII as inducers of activator protein-1 (AP-1) DNA binding activity and/or AP-1-dependent gene transcription in human cells [9].
Human hepatocytes exposed in vitro to iAsIII produce both MAsIII and DMAsIII [10]. Hence, the liver is a source of methylated trivalent arsenicals found in the urine of individuals chronically exposed to iAs in drinking water [11-13]. AsIII-methyltransferase (Cyt19), the enzyme that catalyzes the methylation of iAs, has recently been purified, characterized, and cloned [14]. Our current studies examine the role of AsIII-methyltransferase in the production of methylated trivalent arsenicals and of genetic polymorphisms of this enzyme in human populations. Linking AsIII-methyltransferase genotypes with phenotypes (metabolic patterns and health effects of iAs) will make it possible to identify individuals and subpopulations with an increased risk of developing cancer as a result of chronic exposure to iAs.
Taken together, these findings suggest that the biomethylation of iAs generates toxic and biologically active metabolites with a broad spectrum of potentially adverse effects (Schema II). Although the methylation pathway has traditionally been viewed as the major detoxification mechanism for iAs, the production of MAsIII and DMAsIII in this pathway should be properly regarded as a mechanism for activation of iAs as a toxin and human carcinogen. (This abstract does not necessarily reflect EPA policy.)