The role of extracellular glutathione (GSH) and membrane-bound y-glutamyltranspeptidase (yGT) as contributory factors in the disposition and toxicity of inorganic mercury (HgCI2, 1 mg kg-', i.p.) was investigated in rats pretreated with acivicin (AT-125, 10 mg kg-I), a y-GT inhibitor.
A high degree of y-GT inhibition (75%) and of protection (90%) against HgCI2-induced nephrotoxicity was obtained in y-GT-inhibited rats 24 h post-treatment. Pretreatment with acivicin affected the fractional distribution profile of m3Hg, 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 z03Hg alone, whereas it decreased by 60% between 4 h and 24 h in y-GT-inhibited rats. In y-GT-inhibited rats treated with HgCI2 the renal and plasma reduced glutathione (GSH) content increased by 68% and 330% respectively, as compared to controls. The y-GT inhibition affected the distribution profile of mercury within urinary proteins, shifting the binding of mercury from the highmolecular-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 y-GT in the renal incorporation, toxicity and excretion of inorganic mercury in rats.
Animals
Female Sprague-Dawley rats (IFFA-CREDO, Saint-Germain-sur-I' Arbresle, France) weighing 200-220 g CCC 026&+37)(/94/03020 1-06