Effect of L-(αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid on urinary excretion of methylmercury in the mouse

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 pretreated with ²⁰³Hg-methylmercury (MM) (0.5 mg/kg) to determine whether increasing urinary GS in this strain would result in a simultaneously increased urinary elimination of MM. Doses at AT-125 ranging from 3.0 to 30 mg/kg increased urinary GS in a dose-related fashion. The peak effect was attained at 2 hr after injection. AT-125 (7.5 mg/kg) increased urinary GS to peak value of 450 μM. When this dose was administered to mice 24 hr after MM, neither the rate of decline in body burden of ²⁰³Hg nor the rate of ²⁰³Hg output into urine or feces varied significantly from control values. A dose of 15 mg of AT-125 per kg increased urinary GS to 1.0 mM and caused a significant increase in urinary excretion of ²⁰³Hg when compared to the 7.5-mg dose group. The greatest effect was seen at the 30-mg AT-125/kg dose which produced a 1.9 mM concentration of total GS in urine and a 2-fold increase in the urinary ²⁰³Hg excretion rate. The dose-dependent changes in urinary excretion elicited by AT-125 were paralleled by increased rates of decline of ²⁰³Hg body burden and decreased rates of excretion in the feces. The results suggest that urinary GS must approach the millimolar range before affecting a redistribution of MM across the luminal membrane.