ToxSci Advance Access originally published online on February 9, 2005
Toxicological Sciences 2005 85(1):468-475; doi:10.1093/toxsci/kfi107
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Tissue Distribution and Urinary Excretion of Inorganic Arsenic and Its Methylated Metabolites in Mice Following Acute Oral Administration of Arsenate
* Pharmacokinetics Branch, Experimental Toxicology Division, Mail Stop B143–01, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, and Toxicology Department, CINVESTAV-IPN, Mexico City, Mexico
Received December 7, 2004; accepted February 2, 2005
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, AsIII) 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 µmol As/kg (sodium arsenate, AsV). 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 µmol 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 µmol 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 AsV that should be considered when investigating mechanisms of arsenic-induced toxicity and carcinogenicity.
Key Words: inorganic arsenic; metabolites; dimethylated arsenic; monomethylated arsenic.
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