title: Mouse arsenic (+3 oxidation state) methyltransferase genotype affects metabolism and tissue dosimetry of arsenicals after arsenite administration in drinking water.
abstract: Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes methylation of inorganic arsenic (iAs) 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 (WT) C57BL/6 mice and female As3mt knockout (KO) 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 KO mice; in red blood cells, summed concentrations of arsenicals were higher in KO than in WT mice. In liver, kidney, and lung, summed concentrations of arsenicals were greater in KO than in WT mice. Although capacity for arsenic methylation is much reduced in KO mice, some mono-, di-, and tri-methylated arsenicals were found in tissues of KO 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.
authors.affiliation: Analytical and Environmental Toxicology Division, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, T6G 2G3, Canada.
authors.forename: Baowei
authors.initials: B
authors.lastname: Chen
authors.forename: Lora L
authors.initials: LL
authors.lastname: Arnold
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
authors.forename: David J
authors.initials: DJ
authors.lastname: Thomas
authors.forename: X Chris
authors.initials: XC
authors.lastname: Le
mesh_terms: D000818:Animals; D018053:Arsenites / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D060766:Drinking Water / Q000737:chemistry; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005838:Genotype; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014018:Tissue Distribution; D014874:Water Pollutants, Chemical / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D018053:Arsenites; D060766:Drinking Water; D014874:Water Pollutants, Chemical; D008780:Methyltransferases; C532135:AS3MT protein, mouse; C015001:arsenite