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BOLISM OF ARSENITE IN CULTURED PRIMARY HEPATOCYTES FROM SIX MAMMALIAN SPECIES
Citation:
WALTON, F., Z. DROBNA, A. HARMON, D. J. THOMAS, AND M. STYBLO. BOLISM OF ARSENITE IN CULTURED PRIMARY HEPATOCYTES FROM SIX MAMMALIAN SPECIES. Presented at 45th Annual Society of Toxicology Meeting 2006, San Diego, CA, March 05 - 09, 2006.
Description:
Inorganic arsenic (iAs) is an environmental toxin and carcinogen. Biomethylation is the major pathway for the metabolism of iAs in many mammalian species, including the human. The liver is considered the primary site for iAs methylation and As (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in this pathway. However, significant interspecies differences exist in both the rate and the pattern for in vivo methylation of iAs. To analyze these differences, we examined the rates and patterns for the methylation iAs by primary hepatocytes from human, rat, mice, dog, rabbit, and rhesus monkey. Here, cultured hepatocytes were exposed to 73As-arsenite (iAsIII; 0.3, 0.9, 3.0, 9.0 and 30 nmol As/mg protein) for 24 hours. Radiolabeled metabolites in cells and culture media were analyzed by TLC. Hepatocytes from all six species methylated iAsIII to methyl-As (MAs) and dimethyl-As (DMAs) metabolites. No trimethyl-As species were found. Similar methylation rates were detected for the lowest iAsIII concentration, regardless of the source of hepatocyte. At higher concentrations, rat, canine, and monkey hepatocytes were considerably more efficient methylators of iAsIII than murine, rabbit and human hepatocytes. The low efficiency of murine, rabbit and human hepatocytes to methylate iAsIII was associated with inhibition of DMAs production by moderate concentrations of iAsIII and with a high retention of iAs and MAs in cells. No significant correlations were found between the methylation rate and the thioredoxin reductase activity or glutathione concentration, two factors that influence the in vitro methylation of iAs by recombinant AS3MT. The methylation rate only poorly correlated with the expression of AS3MT. Thus, other factor are likely responsible for interspecies differences in the methylation of iAsIII in primary hepatocytes. Identification of these factors is the goal of future studies. (This abstract does not reflect U.S. EPA policy.)