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Mouse arsenic (+3 oxidation state) methyltransferase genotype affects metabolism and tissue dosimetry of arsenicals after arsenite administration in drinking water
Cher, B., C. X. Le, C. X. Le, L. M. Arnold, S. M. Cohen, AND D. J. THOMAS. Mouse arsenic (+3 oxidation state) methyltransferase genotype affects metabolism and tissue dosimetry of arsenicals after arsenite administration in drinking water. TOXICOLOGICAL SCIENCES. Society of Toxicology, 124(2):320-6, (2011).
Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes methylation of inorganic arsenic producing a number of methylated arsenic metabolites. Although methylation has been commonly considered a pathway for detoxification of arsenic, some highly reactive methylated arsenicals may contribute to toxicity associated with exposure to inorganic arsenic. Here, adult female wild-type C57BL/6 (WT) mice and female As3mt knockout (KG) mice received drinking water that contained 1, 10 or 25 ppm (mg/L) of arsenite for 33 days and blood, liver, kidney and lung were taken for arsenic speciation. Genotype markedly affected concentrations of arsenicals in tissues. Summed concentrations of arsenicals in plasma were higher in WT than in KG mice; in red blood cells, summed concentrations of arsenicals were higher in KG than in WT mice. In liver, kidney, and lung, summed concentrations of arsenicals were greater in KG than in WT mice. Although capacity for arsenic methylation is much reduced in KG mice, some mono-, di-, and tri-methylated arsenicals were found in tissues of KG mice, likely reflecting the activity of other tissue methyltransferases or preabsorptive metabolism by the microbiota of the gastrointestinal tract. These results show that the genotype for arsenic methylation determines the phenotypes of arsenic retention and distribution, and affects the dose-and organ-dependent toxicity associated with exposure to inorganic arsenic.
This study is part of a continuing investigation of the role of the metabolism of arsenic in its actions as a toxicant and carcinogen. Because the pathway for methylation of arsenic produces a number of intermediates that are more toxic and reactive than any inorganic arsenic species, it is of interest to examine the effects of exposure to specific arsenicals in the As3mt knockout mice, an animal nl0del in which capacity to methylate arsenic is markedly reduced. The work on tissue dosimetry reported in the present ms is part of a larger effort to understand the linkage of kinetic and dynamic factors that underlie the toxicity of arsenic
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION