Formation of methylated oxyarsenicals and thioarsenicals in wild-type and arsenic (+3 oxidation state) methyltransferase knockout mice exposed to arsenate.
Arsenic (+3 oxidation state) methyltransferase (As3mt) plays a central role in the enzymatically catalyzed conversion of inorganic arsenic into methylated metabolites. Most studies of the metabolism and disposition of arsenicals following exposure to inorganic arsenic focus on the formation and fate of methylated oxyarsenicals. However, recent research has shown methylated thioarsenicals to be another important class of metabolites of inorganic arsenic. Here, we report on the presence of methylated oxy- and thioarsenicals in urine and liver from wild-type mice that efficiently methylate inorganic arsenic and from As3mt knockout mice that lack arsenic methyltransferase activity. Following a single oral dose of 0.5 mg of arsenic as arsenate/kg body weight, urine from wild-type mice contained methylated oxyarsenicals and unknown arsenicals. Further analysis identified one unknown arsenical in urine of wild-type mice as dimethylmonothioarsinic acid. In addition, another unknown arsenical in urine of wild-type mice that occurred in the urine of about 20 % of arsenate-treated mice. The presence of low levels of methylated arsenicals in liver digests of As3mt knockout mice may reflect the activity of other methyltransferases or the absorption of methylated arsenicals formed by the microbiota of the gastrointestinal tract. The lack of methylated thioarsenicals in urine of As3mt knockout mice suggests a close link between the processes that form methylated oxy- and thioarsenicals.
Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. narenman@zju.edu.cn
Hua
H
Naranmandura
Kanwal
K
Rehman
X Chris
XC
Le
David J
DJ
Thomas
D000284:Administration, Oral; D000818:Animals; D001149:Arsenates / Q000378:metabolism* / Q000633:toxicity; D001152:Arsenicals / Q000652:urine*; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008745:Methylation; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D013054:Spectrophotometry, Atomic; D013438:Sulfhydryl Compounds / Q000652:urine*
D001149:Arsenates; D001152:Arsenicals; D013438:Sulfhydryl Compounds; C518667:dimethylmonothioarsinic acid; D002101:Cacodylic Acid; D008780:Methyltransferases; C532135:AS3MT protein, mouse; C025657:arsenic acid