Accelerated methylmercury elimination in gamma-glutamyl transpeptidase-deficient mice.
The disposition and toxicity of methylmercury, a ubiquitous environmental pollutant, is modulated by binding to the endogenous tripeptide glutathione (GSH) and metabolism of the resulting methylmercury-glutathione complex by the ectoproteins gamma-glutamyl transpeptidase (GGT) and dipeptidase. To evaluate the role of GGT in the whole-body disposition of methylmercury, we compared the elimination of [203Hg]methylmercury in GGT-deficient mice with that in wild-type mice and mice heterozygous for this deficiency. The effects of N-acetylcysteine (NAC), a drug used to maintain the cysteine and GSH levels of GGT-deficient mice, were also examined. Female mice were treated with either 0.5 or 25 micromol of CH3 203HgCl/kg body weight, in the presence and absence of 10 mg/ml NAC in the drinking water. There were no differences in methylmercury excretion between the wild-type and heterozygous mice; however, the GGT-deficient mice excreted methylmercury more rapidly at both dose levels. Wild-type and heterozygous mice excreted from 11 to 24% of the dose in the first 48 hours, whereas the GGT-deficient mice excreted 55 to 66% of the dose, with most of the methylmercury being excreted in urine. Urinary methylmercury excretion was further accelerated in mice that received NAC. In contrast to methylmercury, the whole-body elimination of inorganic mercury was not affected by GGT deficiency, although the tissue distribution of inorganic mercury was markedly different in GGT-deficient male mice, with only 13% of the 203Hg body burden in the kidneys of GGT-deficient mice versus approximately 50% in kidneys of wild-type male mice. These findings provide direct evidence for a major role of GGT in regulating the tissue distribution and elimination of methylmercury and inorganic mercury and provide additional support for the use of NAC as an antidote in methylmercury poisoning.
Ballatori
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Department of Environmental Medicine, University of Rochester School of Medicine, New York 14642, USA. ballatorin@envmed.rochester.edu
Wang
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W
Lieberman
M W
MW
D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008628:Mercury / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008767:Methylmercury Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout; D014018:Tissue Distribution; D005723:gamma-Glutamyltransferase / Q000172:deficiency / Q000502:physiology*
D008767:Methylmercury Compounds; D005723:gamma-Glutamyltransferase; D008628:Mercury; D005978:Glutathione; D000111:Acetylcysteine