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

The gamma-GTP inhibitor L-(alpha S,5S)-alpha-amino-3-chloror-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 microM. 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.