GROWTH-RETARDATION AND CYSTEINE DEFICIENCY IN GAMMA-GLUTAMYL TRANSPEPTIDASE-DEFICIENT MICE

gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes th e first step in the cleavage of glutathione (GSH) and plays an essenti al role in the metabolism of GSH and GSH conjugates of carcinogens, to xins, and eicosanoids. To learn more about the role of GGT in metaboli sm in vivo, we used embryonic stem cell technology to generate GGT-def icient (GGT(m1)/GGT(m1)) mice. GGT-deficient mice appear normal at bir th but grow slowly and by 6 weeks are about half the weight of wild-ty pe 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 GGT(m1)/GGT(m1) mice are elevated 6-fold and 2500-fo ld, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGT(m1)/GGT(m1) mice are reduced to approximate to 20% of wild-typ e mice. Oral administration of N-acetylcysteine to GGT(m1)/GGT(m1) mic e results in normal growth rates and partially restores the normal ago uti coat color. These findings demonstrate the importance of GGT and t he gamma-glutamyl cycle in cysteine and GSH homeostasis.