Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice
Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice
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DOI：
10.1073/pnas.93.15.7923
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发表时间：
1996-07-23
影响因子：
11.1
通讯作者：
Matzuk, MM
中科院分区：
文献类型：
--
作者：
Lieberman, MW;Wiseman, AL;Matzuk, MM
γ-谷氨酰转肽酶（GGT）是一种胞外酶，催化谷胱甘肽（GSH）裂解的第一步，并在致癌物、毒素和类花生酸的GSH和GSH结合物的代谢中发挥重要作用。为了了解更多关于GGT在体内代谢中的作用，我们使用胚胎干细胞技术产生GGT缺陷（GGT（m1）/GGT（m1））小鼠。GGT缺陷小鼠在出生时看起来正常，但生长缓慢，到6周时体重约为野生型小鼠的一半。他们是性不成熟，发展白内障，并有灰色的外套。大多数人在10到18周之间死亡。与野生型小鼠相比，GGT（m1）/GGT（m1）小鼠的血浆和尿液GSH水平分别升高6倍和2500倍。在眼睛、肝脏和胰腺中，组织GSH水平显著降低。GGT（m1）/GGT（m1）小鼠的血浆半胱氨酸水平降低至野生型小鼠的约20%。经口给予GGT（m1）/GGT（m1）小鼠N-乙酰半胱氨酸可导致正常生长速率，并部分恢复正常的琼脂糖被毛颜色。这些发现证明了GGT和γ-谷氨酰循环在半胱氨酸和GSH稳态中的重要性。
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 (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 approximate 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 gamma-glutamyl cycle in cysteine and GSH homeostasis.