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Interpretation of inorganic arsenic metabolism in humans in the light of observations made in vitro and in vivo in the rat
Author(s) -
Buchet J. P.,
Lauwerys R.
Publication year - 1994
Publication title -
applied organometallic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.53
H-Index - 71
eISSN - 1099-0739
pISSN - 0268-2605
DOI - 10.1002/aoc.590080306
Subject(s) - chemistry , arsenic , methylation , in vivo , biotransformation , glutathione , metabolism , biochemistry , excretion , stimulation , arsenic trioxide , urine , toxicokinetics , enzyme , organic chemistry , endocrinology , biology , microbiology and biotechnology , gene
The toxicity of inorganic trivalent arsenic for living organisms is reduced by in vivo methylation of the element. In man, this biotransformation leads to the synthesis of monomethylarsonic (MMA) and dimethylarsinic (DMA) acids, which are efficiently eliminated in urine along with the unchanged form (As i ). In order to document the methylation process in humans, the kinetics of As i , MMA and DMA elimination were studied in volunteers given a single dose of one of these three arsenicals or repeated doses of As i . The arsenic methylation efficiency was also assessed in subjects acutely intoxicated with arsenic trioxide (As 2 O 3 ) and in patients with liver diseases. Several observations in humans can be explained by the properties of the enzymic systems involved in the methylation process which we have characterized in vitro and in vivo in rats as follows: (1) production of As i metabolites is catalyzed by an enzymic system whose activity is highest in liver cytosol; (2) different enzymic activities, using the same methyl group donor ( S ‐adenosylmethionine), lead to the production of mono‐ and di‐methylated derivatives which are excreted in urine as MMA and DMA; (3) dimethylating activity is highly sensitive to inhibition by excess of inorganic arsenic; (4) reduced glutathione concentration in liver moderates the arsenic methylation process through several mechanisms, e.g. stimulation of the first methylation reaction leading to MMA, facilitation of As i uptake by hepatocytes, stimulation of the biliary excretion of the element, reduction of pentavalent forms before methylation, and protection of a reducing environment in the cells necessary to maintain the activity of the enzymic systems.