Dose-Dependent Effects on the Disposition of Monomethylarsonic Acid and Dimethylarsinic Acid in the Mouse After Intravenous Administration

Abstract

The organic arsenicals monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) are the primary metabolites of inorganic arsenic, a known human carcinogen. The objective of this study was to examine if dose would affect the excretion and terminal tissue disposition of MMA and DMA in the mouse. 14C-MMA (4.84 and 484 mumol/kg) and -DMA (8.04 and 804 mumol/kg) were administered to female mice via the tail vein. The mice were placed in metabolism cages for collection of urine (1, 2, 4, 8, 12, and 24 h) and feces (24 h). The animals were then sacrificed at 24 h and tissues were removed and analyzed for radioactivity. The urine was also analyzed for parent compound and metabolites. Urinary excretion of MMA- and DMA-derived radioactivity predominated over fecal excretion. Dose did not affect the overall urinary excretion of both compounds. However, fecal excretion was significantly lower in the low-dose MMA-treated animals as opposed to in the high-dose group, whereas in the high-dose DMA-treated group excretion was lower than in the low-dose DMA group. The retention of radioactivity was low (< 2% of dose) and the distribution pattern similar for both compounds, with carcass > liver > kidney > lung. The concentration of radioactivity (% dose/g tissue) was greater in kidney than in liver, lung, and blood for both compounds. The distribution and concentration of MMA-derived radioactivity was significantly greater in the liver and lung of the high-dose group. The MMA-treated animals excreted predominantly MMA in urine and lower amounts of DMA (< 10% of the dose). The percentage excreted as DMA was significantly higher in the low-dose MMA group. In the urine of DMA-treated animals, an unstable metabolite and the parent compound were detected. Overall, it appears the dose of organic arsenical administered has a minimal effect on its excretion and terminal tissue disposition in the mouse. The rapid elimination and low retention of MMA and DMA explain in part their low acute toxicity.

Individual differences in arsenic metabolism and lung cancer in a case-control study in Cordoba, Argentina

“…Until recently, methylation of InAs was thought to be primarily a detoxification pathway since the methylated species most commonly found in human urine, MMA5 and DMA5, are more water soluble, more readily excreted, and less acutely toxic than InAs (Buchet et al , 1981a; Buchet et al , 1981b; Moore et al , 1997; Hughes and Kenyon, 1998; Gebel, 2002). MMA3 and DMA3 are highly unstable in human urine and so have been measured in only a few human studies.…”

Metabolism of Low-Dose Inorganic Arsenic in a Central European Population: Influence of Sex and Genetic Polymorphisms

“…The metabolism of iAs involves both detoxification (methylation) and activation (reduction). Although MA(V) and DMA(V) have a lower toxicity than inorganic arsenic species (Hughes and Kenyon 1998), the trivalent methylated metabolites are more reactive and toxic than the other arsenic metabolites (Kligerman and Tennant 2006; Petrick et al 2000; Schwerdtle et al 2003a, 2003b; Styblo et al 2000; Vega et al 2001). A series of studies reported the presence of methylarsonite [MA(III)] and dimethylarsinite [DMA(III)] in urine (Aposhian et al 2000; Le et al 2000; Mandal et al 2001; Valenzuela et al 2005), although high concentrations are not likely to be found in urine because the high reactivity renders them to bind in tissues (Vahter 2002).…”

Dietary Intake and Arsenic Methylation in a U.S. Population

“…This was based on the finding that MMA5 and DMA5—the most common forms of MMA and DMA found in exposed humans—are more readily excreted and less toxic than is InAs (Buchet et al 1981; Gebel 2002; Hughes and Kenyon 1998; Moore et al 1997). The trivalent forms of MMA and DMA are rapidly oxidized in urine and therefore are difficult to measure in human epidemiologic studies.…”