TY - JOUR
T1 - Accelerated methylmercury elimination in γ-glutamyl transpeptidase- deficient mice
AU - Ballatori, Nazzareno
AU - Wang, Wei
AU - Lieberman, Michael W.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 1998/4
Y1 - 1998/4
N2 - 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 γ-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 μmol 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 ~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.
AB - 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 γ-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 μmol 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 ~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.
UR - http://www.scopus.com/inward/record.url?scp=0031896518&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031896518&partnerID=8YFLogxK
M3 - Article
C2 - 9546365
AN - SCOPUS:0031896518
VL - 152
SP - 1049
EP - 1055
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -