Lieberman M W, Wiseman A L, Shi Z Z, Carter B Z, Barrios R, Ou C N, Chévez-Barrios P, Wang Y, Habib G M, Goodman J C, Huang S L, Lebovitz R M, Matzuk M M
Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7923-6. doi: 10.1073/pnas.93.15.7923.
gamma-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 approximately 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 gamma-glutamyl cycle in cysteine and GSH homeostasis.
γ-谷氨酰转肽酶（GGT）是一种外切酶，催化谷胱甘肽（GSH）裂解的第一步，在GSH以及致癌物、毒素和类花生酸的GSH共轭物的代谢中起重要作用。为了更多地了解GGT在体内代谢中的作用，我们利用胚胎干细胞技术培育出了GGT缺陷型（GGTm1/GGTm1）小鼠。GGT缺陷型小鼠出生时看似正常，但生长缓慢，到6周时体重约为野生型小鼠的一半。它们性发育不成熟，会患白内障，毛发呈灰色。大多数在10至18周之间死亡。与野生型小鼠相比，GGTm1/GGTm1小鼠血浆和尿液中的GSH水平分别升高了6倍和2500倍。眼睛、肝脏和胰腺中的组织GSH水平显著降低。GGTm1/GGTm1小鼠血浆中的半胱氨酸水平降至野生型小鼠的约20%。给GGTm1/GGTm1小鼠口服N-乙酰半胱氨酸可使其生长速度正常，并部分恢复正常的刺豚鼠毛色。这些发现证明了GGT和γ-谷氨酰循环在半胱氨酸和GSH体内平衡中的重要性。
