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TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ACUTE ORAL ADMINISTRATION OF ARSENATE
Citation:
KENYON, E. M., L. M. DEL RAZO, AND MICHAEL F. HUGHES. TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ACUTE ORAL ADMINISTRATION OF ARSENATE. TOXICOLOGICAL SCIENCES. Oxford University Press, Cary, NC, 85:468-475, (2005).
Description:
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 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 and 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 �mol/kg sodium arsenate (As(V)). Compared to other organs, blood concentrations of iAs, MMA and 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 one hour post dosing. Inorganic As was the predominant arsenical in liver and kidney up to one and two hours post dosing with 10 and 100 �mol/kg, respectively. At later times, DMA was the predominant metabolite in liver and kidney. By one hour 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 two hours post dosing for both dose levels. Notably, DMA was the predominant metabolite in lung at all time points following dosing with 10 �mol/kg. DMA concentration in lung equaled or exceeded that of other tissues from 4 hours post dosing onward for both dose levels. These data demonstrate distinct organ-specific differences in the distribution and methylation of iAs and its metabolites that should be considered when investigating mechanisms of arsenic-induced toxicity and carcinogenicity.