Role of extracellular glutathione and γ-Glutamyltranspeptidase in the disposition and kidney toxicity of inorganic mercury in rats

The role of extracellular glutathione (GSH) and membrane‐bound γ‐glutamyltranspeptidase (γ‐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 γ‐GT inhibitor. A high degree of γ‐GT inhibition (75%) and of protection (90%) against HgCl2‐induced nephrotoxicity was obtained in γ‐GT‐inhibited rats 24 h post‐treatment. Pretreatment with acivicin affected the fractional distribution profile of 203Hg, 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 203Hg alone, whereas it decreased by 60% between 4 h and 24 h in γ‐GT‐inhibited rats. In γ‐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 γ‐GT inhibition affected the distribution profile of mercury within urinary proteins, shifting the binding of mercury from the inghmolecular‐weight fraction (3% against 80%) to the low‐molecular‐weight fraction (72% against 10%). A significant but less impressive shift of mercury from the ingh‐ 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 γ‐GT in the renal incorporation, toxicity and excretion of inorganic mercury in rats.