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

Abstract

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.