Study of inorganic arsenic methylation by rat liver in vitro: relevance for the interpretation of observations in man

Abstract

The biotransformation of inorganic arsenic by rat liver in vitro leads to the production of a monomethylated and a dimethylated arsenic derivative, measured by flameless atomic absorption as monomethylarsonic (MMA) and dimethylarsinic (DMA) acids respectively. The methylating activity is localized in the cytosol and accepts only As3+ as substrate. Its optimum pH lies between 7.5 and 8.0, and reduced glutathione (10(-2)M) is required for full activity. S-Adenosylmethionine is the essential methyl group donor and corrinoïd derivatives act synergistically. An excess of substrate and the addition of mercuric ions prevent the formation of the dimethylated arsenic derivative without affecting that of the monomethylated compound. This indicates that two different enzymatic activities are involved in the methylation of inorganic arsenic in mammals. Previous observations in man (Buchet et al. 1981 b, 1984) and the results of the present study suggest that DMA production results from the subsequent methylation of the MMA precursor, although the possibility that metabolites are also produced by two completely independent pathways cannot yet be conclusively rejected. The kinetics of MMA and DMA production provide an explanation for the observations that in volunteers given increasing amounts of As3+, the urinary excretion of DMA levels off faster than that of MMA and in patients acutely intoxicated with As3+, several days may elapse before DMA becomes the preponderant metabolite. The results of the present study also suggest that the reduction of MMA production associated with an increased synthesis of DMA found in patients with liver diseases given a standard dose of As3+ might be due to a reduction of As3+ uptake by the liver cells.