Growth retardation and cysteine deficiency in γ-glutamyl transpeptidase-deficient mice

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 (GGT^m1/GGT^m1) 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 GGT^m1/GGT^m1 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 GGT^m1/GGT^m1 mice are reduced to ~20% of wild-type mice. Oral administration of N-acetylcysteine to GGT^m1/GGT^m1 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.