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.

Arsenicals in maternal and fetal mouse tissues after gestational exposure to arsenite

“…Accumulation and retention of DMAs in fetal tissues could reflect an unusual affinity of some tissue constituent for DMAs. Preferential accumulation of DMAs occurs in lungs of rodents exposed to iAs or DMAs (Marafante et al, 1987;Hughes et al, 2000;Kenyon et al, 2005). Accumulation of DMAs in lung produces morphological changes and cellular toxicity (Yamanaka and Okada, 1994;Kato et al, 2000), although, critical molecular targets in tissues for iAs and its metabolites have not been identified.…”

Toxicology and Epidemiology of Arsenic and its Compounds

“…Once in systemic circulation, arsenic is rapidly cleared from blood and distributed to all major organs in the body in most common laboratory animals, including mice, rabbits, and hamsters (Vahter and Norin, 1980;Marafante, Bertolero and Edel, 1982;Marafante, Vahter and Envall, 1985;Yamauchi and Yamamura, 1985;Kenyon, Del Razo and Hughes, 2005a;Kenyon, Del Razo and Hughes, 2005b). In humans, inorganic arsenic is also rapidly cleared from blood with a half-life of about two hours.…”

“…Although clearance of both inorganic As(V) and inorganic As(III) from blood is rapid, both valance state and dose-dependent differences have been observed (Vahter and Norin, 1980;Kenyon, Del Razo and Hughes, 2005a;Kenyon, Del Razo and Hughes, 2005b). Vahter and Norin (1980) reported that at a high oral dose of arsenic (4 mg As kg −1 ), inorganic As(III)-dosed mice had a higher erythrocyte to plasma ratio of approximately 2-3, whereas in inorganic As(V)-dosed mice the ratio was much closer to one.…”

Presencia de altos niveles de arsénico en tejidos cardiovasculares de pacientes de áreas contaminadas en Chile

“…El As inorgánico es la fracción química más toxica, se encuentra en dos estados de oxidación 3 y 5. El As inorgánico es metilado a formas menos tóxicas, Monometilarsenato (MMA) y Dimetilarsinato (DMA), que además son excretables 13,14 . Sin embargo, se presentan considerables variaciones entre la concentración de estas especies químicas en poblaciones grupales15.…”

“…El As orgánico tiene formas no tóxicas, que se encuentran presentes en tejidos biológicos humanos; posiblemente son consecuencia de especies más estabilizadas de As que provienen exclusivamente de la ingestión de alimentos, como es el caso de la Arsenocolina (AsC) y Arsenobetaina (AsB), asociadas generalmente con los alimentos de origen marino 21 , los cuales siguen un mecanismo de biotransformación conocido en mamíferos 22,23 . La información disponible indica que un porcentaje mayor de estos organometálicos es excretado 13,14 . Parece no ser necesario poner atención en otros organometálicos además de MMA y DMA, en relación con su eventual asociación con el riesgo de ECV.…”