Glutathione-dependent antioxidant system in diabetes-induced embryopathy.

我们已经证明，在器官发生的关键时期，高血糖诱导的胚胎畸形的机制是通过增加自由基的形成和谷胱甘肽（GSH）的消耗来介导的（Diabetes 44: 992-998,1995）。研究谷胱甘肽酯对糖尿病胚胎畸形的影响。链脲佐菌素诱导的糖尿病妊娠大鼠胚胎畸形发生率增加（21.2 vs 2.2%, p<0.01）。从糖尿病妊娠大鼠身上提取的分离胚胎细胞中自由基形成增加。与正常妊娠大鼠相比，糖尿病妊娠大鼠胚胎中谷胱甘肽浓度明显降低。妊娠糖尿病大鼠胚胎谷胱甘肽合成酶γ -谷氨酰系统氨酸合成酶（γ - gcs）活性在氧化应激条件下无显著升高。为了验证谷胱甘肽耗竭在糖尿病诱导的畸形中起关键作用的假设，我们在妊娠6-11天期间给糖尿病妊娠大鼠腹腔注射谷胱甘肽酯。给妊娠糖尿病大鼠注射谷胱甘肽酯可以恢复胚胎中谷胱甘肽的浓度，减少自由基种类，从而降低胚胎畸形的发生率（1.1 vs 21.2%, p<0.01）。这些结果表明，胚胎在器官发生的主要时期，谷胱甘肽的消耗和氧化应激下谷胱甘肽合成酶的反应受损在糖尿病妊娠的胚胎畸形中起重要作用。

We have shown that the mechanism of hyperglycemia-induced embryonic malformations is mediated through increaced free radical formations and glutathione (GSH) depletion in embryo during the critical periods of organogenesis (Diabetes 44 : 992-998,1995).We investigated effect of GSH-ester administration on diabetes-induced embryonic malformations. Embryos from streptozotocin-induced diabetic pregnant rats showed increased frequency of embryonic malformations (21.2 vs 2.2%, p<0.01). Free radical formations increased in isolated embryonic cells taken from diabetic pregnant rats. The concentration of GSH in embryos from diabetic pregnant rats was significantly decreased compared with normal pregnant rats. The activities of gamma-glutamyl systein synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme, in embryos from pregnant diabetic rat did not significantly increased against oxidative stress. To test hypothesis that GSH depletion in crucial role on diabetes-induced malformations, GSH ester was administered intraperitoneally in diabetic pregnant rats during gestational days 6-11. Administration of GSH ester to pregnant diabetic rats restored GSH concentrations in these embryos and reduced free radical species leading to reduced incidence of embryonic malformations (1.1 vs 21.2%, p<0.01). These results indicate that an embryo during main periods of organogenesis, GSH depletion and impaired response of GSH synthesizing enzyme despite oxidative stress has crucial role in embryonic malformation in deabetic pregnancy.