TY - JOUR
T1 - Growth retardation and cysteine deficiency in γ-glutamyl transpeptidase-deficient mice
AU - Lieberman, Michael W.
AU - Wiseman, Amy L.
AU - Shi, Zheng-Zheng
AU - Carter, Bing Z.
AU - Barrios, Roberto
AU - Ou, Ching Nan
AU - Chévez-Barrios, Patricia
AU - Wang, Yan
AU - Habib, Geetha M.
AU - Goodman, J. Clay
AU - Huang, Shiu L.
AU - Lebovitz, Russell M.
AU - Matzuk, Martin M.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1996/7/23
Y1 - 1996/7/23
N2 - γ-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice. GGT-deficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTm1/GGTm1 mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGTm1/GGTm1 mice are reduced to ~20% of wild-type mice. Oral administration of N-acetylcysteine to GGTm1/GGTm1 mice results in normal growth rates and partially restores the normal agouti coat color. These findings demonstrate the importance of GGT and the γ-glutamyl cycle in cysteine and GSH homeostasis.
AB - γ-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice. GGT-deficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTm1/GGTm1 mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGTm1/GGTm1 mice are reduced to ~20% of wild-type mice. Oral administration of N-acetylcysteine to GGTm1/GGTm1 mice results in normal growth rates and partially restores the normal agouti coat color. These findings demonstrate the importance of GGT and the γ-glutamyl cycle in cysteine and GSH homeostasis.
KW - cataracts
KW - glutathione
KW - homologous recombination
KW - N-acetylcysteine
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U2 - 10.1073/pnas.93.15.7923
DO - 10.1073/pnas.93.15.7923
M3 - Article
C2 - 8755578
AN - SCOPUS:16044374704
VL - 93
SP - 7923
EP - 7926
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 15
ER -