title: Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in mice following acute oral administration of arsenate.
abstract: The relationship of exposure dose and tissue concentration of parent chemical and metabolites is a critical issue in cases where toxicity may be mediated by a metabolite or by parent chemical and metabolite acting together. This has emerged as an issue for inorganic arsenic (iAs), because both its trivalent and pentavalent methylated metabolites have unique toxicities; the methylated trivalent metabolites also exhibit greater potency than trivalent inorganic arsenic (arsenite, As(III)) for some endpoints. In this study, the time-course tissue distributions for iAs and its methylated metabolites were determined in blood, liver, lung, and kidney of female B6C3F1 mice given a single oral dose of 0, 10, or 100 micromol As/kg (sodium arsenate, As(V)). Compared to other organs, blood concentrations of iAs, mono- (MMA), and dimethylated arsenic (DMA) were uniformly lower across both dose levels and time points. Liver and kidney concentrations of iAs were similar at both dose levels and peaked at 1 h post dosing. Inorganic As was the predominant arsenical in liver and kidney up to 1 and 2 h post dosing, with 10 and 100 micromol As/kg, respectively. At later times, DMA was the predominant metabolite in liver and kidney. By 1 h post dosing, concentrations of MMA in kidney were 3- to 4-fold higher compared to other tissues. Peak concentrations of DMA in kidney were achieved at 2 h post dosing for both dose levels. Notably, DMA was the predominant metabolite in lung at all time points following dosing with 10 micromol As/kg. DMA concentration in lung equaled or exceeded that of other tissues from 4 h post dosing onward for both dose levels. These data demonstrate distinct organ-specific differences in the distribution and methylation of iAs and its methylated metabolites after exposure to As(V) that should be considered when investigating mechanisms of arsenic-induced toxicity and carcinogenicity.
authors.affiliation: Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. kenyon.elaina@epa.gov
authors.forename: E M
authors.initials: EM
authors.lastname: Kenyon
authors.forename: L M
authors.initials: LM
authors.lastname: Del Razo
authors.forename: M F
authors.initials: MF
authors.lastname: Hughes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001149:Arsenates / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine*; D001152:Arsenicals / Q000652:urine*; D002101:Cacodylic Acid / Q000652:urine*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008658:Inactivation, Metabolic; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D001149:Arsenates; D001152:Arsenicals; D002101:Cacodylic Acid; C020300:monomethylarsonic acid