Possible role of hepatic glutathione in transport of methylmercury into mouse kidney.
The mechanism of the renal uptake of methylmercury was studied in mice. Preadministration of 1,2-dichloro-4-nitrobenzene (DCNB), which is a reagent that depletes hepatic glutathione (GSH) without affecting the renal GSH level, 30 min before injection of methylmercury significantly decreased the renal accumulation of mercury. The renal accumulation of mercury in mice receiving methylmercury-GSH intravenously was significantly higher than that in mice receiving methylmercuric chloride. These results suggest the possibility that hepatic GSH, as a source of extracellular GSH, plays an important role in the renal accumulation of methylmercury. No significant difference in renal mercury accumulation between bile duct-cannulated mice and normal mice was observed, indicating that the enterohepatic circulation of methylmercury is not an important factor in the renal accumulation of methylmercury in mice. Pretreatment of mice with acivicin, a potent inhibitor of gamma-glutamyl transpeptidase (gamma-GTP), significantly depressed the renal uptake of methylmercury and increased the urinary excretion of GSH and methylmercury. In in vitro reactions, methylmercury-GSH was degraded into methylmercury-cysteinylglycine by gamma-GTP, and this product was then converted to methylmercury-cysteine by dipeptidase. These results suggest that methylmercury is transported into the kidney as a complex with GSH, and then incorporated into the renal cells after degradation of the GSH moiety by gamma-GTP and dipeptidase, although the methylmercury bound to extracellular GSH can be reversibly transferred to plasma proteins in the bloodstream.
Naganuma
A
A
Department of Public Health, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Oda-Urano
N
N
Tanaka
T
T
Imura
N
N
D000818:Animals; D001692:Biological Transport; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000502:physiology*; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008631:Mercury Radioisotopes; D008767:Methylmercury Compounds / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009578:Nitrobenzenes / Q000494:pharmacology*
D007555:Isoxazoles; D008631:Mercury Radioisotopes; D008767:Methylmercury Compounds; D009578:Nitrobenzenes; C028328:1,2-dichloro-4-nitrobenzene; D005978:Glutathione; C006303:acivicin