Interindividual variation in the metabolism of arsenic in cultured primary human hepatocytes


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Abstract

Liver is a prime site for conversion of inorganic arsenic (iAs) to methylated metabolites, including methylarsenicals (MAs) and dimethylarsenicals (DMAs). To assess interindividual variation in the capacity of liver to metabolize iAs, we examined the metabolic fate of arsenite (iAsIII) in normal primary human hepatocytes obtained from eight donors and cultured under standard conditions. Methylation rates, yields, and distribution of arsenicals were determined for hepatocytes exposed to 0.3–30 nmol of iAsIII/mg of protein for 24 h. Although the accumulation of arsenic (As) by cells was a linear function of the initial concentration of iAsIII in culture, the concentration of As retained in cells varied several fold among donors. DMAs was the major methylated metabolite found in cultures exposed to low concentrations of iAsIII; at higher concentrations, MAs was always predominant. Maximal rates for methylation of iAsIII were usually attained at 3 or 9 nmol of iAsIII/mg of protein and varied about 7-fold among donors. For most donors, the methylation rate decreased at the highest iAsIII concentrations. MAs was the major methylated metabolite retained in cells regardless of exposure level. DMAs was the major methylated metabolite found in medium. The interindividual differences in rates for iAsIII methylation were not strictly associated with variations in basal mRNA levels for cyt19, an As-methyltransferase. Analysis of the coding sequence of cyt19 identified one heterozygote with Met287Thr mutation in a single allele. Thus, genetic polymorphism of cyt19 along with other cellular factors is likely responsible for interindividual differences in the capacity of primary human hepatocytes to retain and metabolize iAsIII.

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