Factors influencing arsenic methylation in humans

Abstract

Most mammals metabolize inorganic arsenic to methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by stepwise transfer of methyl groups from S-adenosylmethionine to arsenic in its trivalent oxidation state. The methylated metabolites are less reactive with tissue components, less toxic, and more readily excreted in the urine than is inorganic arsenic. There are marked differences in arsenic metabolism between mammalian species and between human population groups and individuals. We are studying arsenic metabolism in people of native Andean origin or mixed ethnic origin exposed to arsenic in drinking water (200 μg As/L) in northern Argentina. These people have a unique metabolism of arsenic in that they excrete only a few percent MMA in the urine. All other population groups studied so far have an average urinary metabolite distribution of inorganic arsenic, MMA, and DMA of about 20:15:65. However, the interindividual variation is extensive. This may indicate the existence of genetic polymorphism in the expression of arsenic methyltransferases. The toxicological significance of the observed differences in formation of MMA and DMA is not clear. In the populations studied, arsenic methylation was influenced by age, exposure level, and pregnancy. The relative percentage of urinary DMA was lower in children than in adults, which may indicate that children retain more arsenic in their tissues and, therefore, are more sensitive to arsenic exposure. In the children, there was an increase in % DMA with increasing exposure level, indicating an induction of the methylation of arsenic. Previous studies on adult populations in Chile and Mexico indicate a decrease in the relative amount of DMA in urine and a corresponding increase in inorganic arsenic and MMA, with increasing exposure levels. In the Argentinean population groups, arsenic was shown to be transferred to the fetus, in line with previously published data from experimental animal studies. There was a marked increase in the relative amount of DMA in urine at the end of pregnancy, as well as in the newborn infant, indicating induction of arsenic methylation during pregnancy. J.Trace Elem. Exp. Med. 13:173–184, 2000. © 2000 Wiley-Liss, Inc.