Role of extracellular glutathione and gamma-glutamyltranspeptidase 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. Pretreatment with acivicin affected the fractional distribution profile of 203 Hg, resulting in a twofold decrease in the renal incorporation of mercury 4 h post-treatment 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 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.
de Ceaurriz
J
J
Laboratoire de Chimie-Toxicologie de l'Environnement, Faculté de Pharmacie, Chatenay-Malabry, France.
Payan
J P
JP
Morel
G
G
Brondeau
M T
MT
D000818:Animals; D002850:Chromatography, Gel; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D008627:Mercuric Chloride / Q000493:pharmacokinetics* / Q000633:toxicity*; D008631:Mercury Radioisotopes; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D007555:Isoxazoles; D008631:Mercury Radioisotopes; D013438:Sulfhydryl Compounds; D008627:Mercuric Chloride; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin