Ischemia-reperfusion (IR) injury is a major clinical problem and is associated with numerous adverse effects. GGsTop [2-amino-4{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid] is a highly specific and irreversible γ-glutamyl transpeptidase (γ-GT) inhibitor. We studied the protective effects of GGsTop on IR-induced hepatic injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. Before clamping, saline (IR group) or saline containing 1 mg/kg body wt of GGsTop (IR-GGsTop group) was injected into the liver through the inferior vena cava. At 90 min of ischemia, blood flow was restored. Blood was collected before induction of ischemia and prior to restoration of blood flow and at 12, 24, and 48 h after reperfusion. All the animals were euthanized at 48 h after reperfusion and the livers were harvested. Serum levels of alanine transaminase, aspartate transaminase, and γ-GT were significantly lower after reperfusion in the IR-GGsTop group compared with the IR group. Massive hepatic necrosis was present in the IR group, while only few necroses were present in the IR-GGsTop group. Treatment with GGsTop increased hepatic GSH content, which was significantly reduced in the IR group. Furthermore, GGsTop prevented increase of hepatic γ-GT, malondialdehyde, 4-hydroxynonenal, and TNF-α while all these molecules significantly increased in the IR group. In conclusion, treatment with GGsTop increased glutathione levels and prevented formation of free radicals in the hepatic tissue that led to decreased IR-induced liver injury. GGsTop could be used as a pharmacological agent to prevent IR-induced liver injury and the related adverse events.

中文翻译：

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GGsTop是一种新型且特异性的γ-谷氨酰转肽酶抑制剂，可保护大鼠肝脏缺血再灌注损伤。

缺血再灌注（IR）损伤是一个主要的临床问题，并与许多不良反应相关。GGsTop [2-氨基-4 {[3-（羧甲基）苯基]（甲基）膦酰基}丁酸]是一种高度特异性且不可逆的γ-谷氨酰转肽酶（γ-GT）抑制剂。我们研究了GGsTop对IR诱导的大鼠肝损伤的保护作用。缺血是通过夹住肝左外侧和正中叶的门静脉和肝动脉而引起的。在钳夹之前，通过下腔静脉将生理盐水（IR组）或含有1 mg / kg体重的GGsTop的生理盐水（IR-GGsTop组）注入肝脏。缺血90分钟后，血流恢复。在诱导缺血之前和恢复血流之前以及再灌注后12、24和48小时收集血液。在再灌注后48小时将所有动物安乐死，并收获肝脏。与IR组相比，IR-GGsTop组在再灌注后的血清丙氨酸转氨酶，天冬氨酸转氨酶和γ-GT水平显着降低。IR组中存在大量肝坏死，而IR-GGsTop组中仅有少量坏死。GGsTop治疗可增加肝脏GSH含量，IR组明显降低。此外，GGsTop阻止了肝脏γ-GT，丙二醛，4-羟基壬烯醛和TNF-α的增加，而所有这些分子在IR组中均显着增加。总之，用GGsTop进行治疗可增加谷胱甘肽水平并防止肝组织中自由基的形成，从而减少IR引起的肝损伤。