title: Arsenic (+3 oxidation state) methyltransferase genotype affects steady-state distribution and clearance of arsenic in arsenate-treated mice.
abstract: 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 0.5mg of arsenic as arsenate per kilogram of 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.
authors.affiliation: Pharmacokinetics Branch, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hughes
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Edwards
authors.forename: Karen M
authors.initials: KM
authors.lastname: Herbin-Davis
authors.forename: Jesse
authors.initials: J
authors.lastname: Saunders
authors.forename: Miroslav
authors.initials: M
authors.lastname: Styblo
authors.forename: David J
authors.initials: DJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001149:Arsenates / Q000493:pharmacokinetics* / Q000633:toxicity; D001151:Arsenic / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D001743:Urinary Bladder / Q000378:metabolism
chemical_list: D001149:Arsenates; D008780:Methyltransferases; C532135:AS3MT protein, mouse; D001151:Arsenic