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INTERINDIVIDUAL VARIATION IN THE METABOLISM OF ARSENIC IN HUMAN HEPATOCYTES
Citation:
Drobna, Z., S. B. Waters, Walton, Felecia S, V. Devesa, E. L. LeCluyse, M Styblo, AND D J. Thomas. INTERINDIVIDUAL VARIATION IN THE METABOLISM OF ARSENIC IN HUMAN HEPATOCYTES. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
The liver is the major site for the enzymatic methylation of inorganic arsenic (iAs) in humans. Primary cultures of normal human hepatocytes isolated from tissue obtained at surgery or from donor livers have been used to study interindividual variation in the capacity of liver to metabolize iAs. To minimize variability related to donor's health status and medication, hepatocytes were cultured under standard conditions for 5 or 6 days before use. This interval allowed cellular functions (redox status and activities of drug metabolizing enzymes) to stabilize and assured the subsequent studies of methylation capacity reflected genotypic and phenotypic variability. Using standardized culture conditions, we compared methylation patterns for iAs in hepatocytes prepared from 7 donors. Methylation rates and yields and distribution of metabolites were determined in cells exposed to arsenite (iAsIII) (0.3, 0.9, 3, 9 or 30 nmol/mg protein) for 24 hours. For most donors, high iAsIII concentrations inhibited methylation (especially DMAs production) and decreased the DMAs/MAs ratio. However, for some donors, methylation was not inhibited even at the highest iAsIII concentrations. Maximal methylation rates (usually in cells at 3 or 9 nmol iAsIII/mg protein) varied from 2.6 to 20 pmol CH3 transferred/mg protein/hour). iAs and MAs were major metabolites retained in cells; iAs and DMAs were the major metabolites in culture media at low iAsIII levels. Statistically significant positive correlations were found between the amounts of iAs and MAs retained in cells and the methylation rate. These data suggest that significant interindividual differences exist in capacities of human liver to methylate iAs. These differences may underlie interindividual variation in susceptibility to toxic and carcinogenic effects of iAs exposure. (This abstract does not reflect EPA policy.)