The absorbed arsenic undergoes hepatic biomethylation to form monomethylar-sonic acid (MMA) and dimethylarsinic acid (DMA) that are less toxic but not totally innocuous.78,79 Methylation of arsenic involves a stepwise process of two-electron reduction of the pentavalent arsenic species (e.g. AsV, MMAV and DMAV) to the trivalent arsenic species (e.g. As111, MMA111 and DMA111), followed by the oxidative addition of a methyl group to the trivalent arsenic species.80 The postulated pathway for biomethylation of arsenic is shown in Figure 16.2. GSH acts as the reducing agent, and S-adenosyl methionine (SAM) as the methyl donor. DMAV is the dominant urinary metabolite (55-80%) compared with MMAV (10-20%) and inorganic arsenic species (10-30%).81 84
HO As OH
Methylarsonic O=As— CH3
- Methyltransferase O (unclassified) O=As-CH3 ^_
Dimethylarsinic SAHC acidV
Figure 16.2 Possible metabolic pathways of inorganic arsenic. GSH - Glutathione; GSSG - Oxidized glutathione; SAM - S-adenosyl methionine; SAHC - S-adenosyl homocysteine
After acute poisoning, the highest concentration of arsenic is in the kidney and liver;85 whereas after chronic arsenic ingestion, arsenic accumulates in the liver, kidneys, heart and lungs, and smaller amounts in muscles, nervous system, gastrointestinal tract and spleen.85 Though most arsenic is cleared from these sites after withdrawal, residual amounts remain in the keratin-rich tissues such as nails, hair and skin.
Trivalent arsenicals, including sodium arsenite and the more soluble As2O3, inhibit many enzymes by reacting with biological ligands that possess available sulfur groups. In all organs, As111 is the main form of arsenic bound to tissues, compared with AsV and the methylated metabolites, which show very weak affinity for tissues and therefore are rapidly eliminated in bile, blood and urine.85,86
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