The major human metabolic pathway for inorganic arsenic is methylation (1-6). Most of the inorganic arsenic, As(III) and As(V), is metabolized to dimethylarsinic acid [DMA(V)] and monomethylarsonic acid [MMA(V)] before excretion in the urine. Because the relative acute toxicity decreases from inorganic arsenite and arsenate [medi-an lethal dose (LD 50) 10-20 mg/kg) to MMA(V) (LD 50 700-1,600 mg/kg) and DMA(V) (LD 50 700-2,600 mg/kg), it has been suggested that the methylation of arsenic in the body is a detoxification pathway (2-6). More recent research argues that the carcinogenic effects of these arsenic compounds are not well understood and may not follow the same decreasing order. Several studies suggest that methylated arsenic species, especially at the trivalent state, may be more toxic than the parent inorganic arsenic compounds (1,7-20). Methylation of arsenic is also implicated in the carcinogenic effects of arsenic because of the possible effects on the methylation of DNA (21,22). Methylation of arsenic involves a two-electron reduction of pentavalent [e.g., As(V) and MMA(V)] to trivalent [e.g., As(III) and MMA(III)] arsenic species followed by the transfer of a methyl group from a methyl donor, such as S-adenosylmethionine (23-25). The reduction and oxidative addition sequence may be summarized in Figure 1. This methylation mechanism has been widely accepted, and the metabolites DMA(V) and MMA(V) have been consistently observed in human urine. A key intermediate for the methylation of MMA(V) to DMA(V) is the MMA(III) species. Several recent studies have indicated the presence of MMA(III) species in rat liver cytosol and hepatocytes and demonstrated the important effects of the methylat-ed trivalent arsenic species in biological systems (16-20,26-29). Although DMA(V), MMA(V), As(V), and inorganic As(III) have been commonly detected in human urine (30-43), the key intermediate metabolite MMA(III), from the methylation of MMA(V) to DMA(V), deserves more attention; however , there is no analytical method for the specia-tion of MMA(III) in human systems. This report describes the speciation of MMA(III) in addition to the usual arsenic species in human urine, As(III), As(V), MMA(V), and DMA(V). Determination of arsenic species in human urine is a measure of recent exposure to arsenic and provides useful information for a better understanding of arsenic metabolism and health effects. Materials and Methods Reagents and standards. Sodium arsenate [As(O)OH(ONa) 2 ⋅ 7H 2 O] and sodium cacodylate [(CH 3) 2 As(O)ONa] were obtained from Sigma (St. Louis, MO, USA), and monomethylarsinate [CH 3 As(O)OHONa] was obtained from Chem Service (West Chester, PA, USA). Stock solutions (1,000 mg As/L) of these arsenicals were prepared by dissolving appropriate amounts of the corresponding arsenic compounds in 0.01 M hydrocholoric acid, and standard solutions were prepared by serial dilution with deion-ized water. An atomic absorption arsenic standard solution (Sigma) containing 1000.0 mg As/L as arsenite in 2% KOH was used as...
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