Mechanisms of Urinary Excretion of Methylmercury (MM)
A two-fold difference in elimination rates of methylmercury (MM) between two genetic variant strains of mice was due to a five-fold greater rate of urinary excretion in the fast-excreting strain. Further investigation indicated that the difference could not be accounted for by biotransformation of MM to the inorganic form. However, several factors that could conceivably influence MM renal excretion were altered, including an increased plasma total glutathione (GS) concentration, and an increased rate of output of GS in the urine. To assess the role that GS may play in the elimination of methylmercury in the urine, the γ-GTP inhibitor, L-[αs,5s]-α-Amino-3-chloro-4,5-Dihydro-5-Isoxazoleacetic Acid (AT-125), was administered to CBA/J mice previously treated with 203Hg-MM to determine whether increasing urinary GS could result in a simultaneous increase in urinary excretion of MM. Increasing doses of AT-125 resulted in a dose-dependent increase in urinary GS. MM excretion, however, did not increase in a direct proportion to increasing concentrations of GS.
Earlier studies in whole blood indicated that millimolar plasma concentrations of low molecular weight thiols were required to redistribute MM from cellular binding sites into plasma. Similarly, increased urinary MM excretion coincided only with the period following AT-125 administration when urinary thiol was elevated to 300 to 500 times normal levels to the millimolar concentration range. These studies suggest that changes in GS elimination into urine may only be of consequence with regard to MM excretion once GS levels have been elevated to the millimolar concentration range.
KeywordsUrinary Excretion Mixed Disulfide Constituent Amino Acid Renal Proximal Tubule Cell Mouse Urine
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