ROLE OF EXTRACELLULAR GLUTATHIONE AND GAMMA-GLUTAMYL-TRANSPEPTIDASE IN THE DISPOSITION AND KIDNEY TOXICITY OF INORGANIC MERCURY IN RATS

The role of extracellular glutathione (GSH) and membrane-bound gamma-glutamyltranspeptidase (gamma-GT) as contributory factors in the disposition and toxicity of inorganic mercury (HgCl2, 1 mg kg(-1), i.p.) was investigated in rats pretreated with acivicin (AT-125, 10 mg kg(-1)), a gamma-GT inhibitor. A high degree of gamma-GT inhibition (75%) and of protection (90%) against HgCl2-induced nephrotoxicity was obtained in gamma-GT-inhibited rats 24 h post-treatment. Pretreatnent with acivicin affected the fractional distribution profile of Hg-203, resulting in a twofold decrease in the renal incorporation of mercury 4 h posttreatment and a threefold increase in the 24-h urinary excretion of mercury. Plasma radioactivity remained constant over 24 h in rats dosed with Hg-203 alone, whereas it decreased by 60% between 4 h and 24 h in gamma-GT-inhibited rats. In gamma-GT-inhibited rats treated with HgCl2 the renal and plasma reduced glutathione (GSH) content increased by 68% and 330% respectively, as compared to controls. The gamma-GT inhibition affected the distribution profile of mercury within urinary proteins, shifting the binding of mercury from the high-molecular-weight fraction (3% against 80%) to the low-molecular-weight fraction (72% against 10%). A significant but less impressive shift of mercury from the high- to the low-molecular-weight fraction also arose in the plasma. These results taken together support the pivotal role of extracellular GSH and membrane-bound gamma-GT in the renal incorporation, toxicity and excretion of inorganic mercury in rats.