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Arsenic (+3 oxidation state) methyltransferase genotype affects steady-state distribution and clearance of arsenic in arsenate-treated mice
Citation:
HUGHES, M. F., B. C. EDWARDS, K. HERBIN-DAVIS, AND D. J. THOMAS. Arsenic (+3 oxidation state) methyltransferase genotype affects steady-state distribution and clearance of arsenic in arsenate-treated mice. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 249(3):217-23, (2010).
Impact/Purpose:
This ms describes the distribution and clearance of arsenic in wild-type and As3mt knockout mice. With repeated oral dosing with arsenate, knockout mice attain higher body burdens than do wild-type . Differences between the two As3mt genotypes may be used to study the modes of action of arsenic as a toxicant and carcinogen.
Description:
Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes formation of mono-, di-, and tri-methylated metabolites of inorganic arsenic. Distribution and retention of arsenic were compared in adult female As3mt knockout mice and wild-type C57BL/6 mice using a regimen in which mice received daily oral doses of 0.5 mg of arsenic as arsenate per kg body weight. Regardless of genotype, arsenic body burdens attained steady state after 10 daily doses. At steady state, arsenic body burdens in As3mt knockout mice were 16 to 20 times greater than in wild type mice. During the post dosing clearance period, arsenic body burdens declined in As3mt knockout mice to ~ 35% and in wild-type mice to ~10% of steady-state levels. Urinary concentration of arsenic was significantly lower in As3mt knockout mice than in wild-type mice. At steady state As3mt knockout mice had significantly higher fractions of the body burden of arsenic in liver, kidney, and urinary bladder than did wild-type mice. These organs and lung had significantly higher arsenic concentrations than did corresponding organs from wild-type mice. Inorganic arsenic was the predominant species in tissues of As3mt knockout mice; tissues from wild-type mice contained mixtures of inorganic arsenic and its methylated metabolites. Diminished capacity for arsenic methylation in As3mt knockout mice prolongs retention of inorganic arsenic in tissues and affects whole body clearance of arsenic. Altered retention and tissue tropism of arsenic in As3mt knockout mice could affect the toxic or carcinogenic effects associated with exposure to this metalloid or its methylated metabolites. This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
