Epperly Michael, Jin Shunqian, Nie Suhua, Cao Shaonan, Zhang Xichen, Franicola Darcy, Wang Hong, Fink Mitchell P, Greenberger Joel S
Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Radiat Res. 2007 Nov;168(5):552-9. doi: 10.1667/RR1009.1.
Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to improve survival and ameliorate organ damage in animal models of sepsis, ischemia/reperfusion injury and hemorrhagic shock. Incubating IL3-dependent mouse hematopoietic progenitor cell 32Dcl3 cells before or after irradiation with 10 mM EP increased resistance to radiation as assessed by clonogenic radiation survival curves, decreased release of mitochondrial cytochrome C into the cytoplasm, and decreased apoptosis. EP inhibited radiation-induced caspase 3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in 32Dcl3 cells in a concentration-dependent fashion. EP was given i.p. to C57BL/6NHsd mice irradiated with 9.75 Gy total-body irradiation (TBI). This treatment significantly improved survival. The survival benefit was apparent irrespective of whether treatment with EP was started 1 h before TBI and continued for 5 consecutive days after TBI or the compound was injected only 1 h before or only for 5 days after TBI. In all of the in vitro and in vivo experiments, ethyl lactate, an inactive analogue of EP, had no detectable radioprotective or mitigating effects. EP may be an effective radioprotector and mitigator of the hematopoietic syndrome induced by TBI.
丙酮酸乙酯（EP）是一种简单的丙酮酸脂肪族酯，已被证明在脓毒症、缺血/再灌注损伤和失血性休克的动物模型中可提高生存率并改善器官损伤。用10 mM EP在照射前或照射后孵育依赖白细胞介素3的小鼠造血祖细胞32Dcl3，通过克隆形成辐射存活曲线评估发现其对辐射的抗性增加，线粒体细胞色素C向细胞质的释放减少，细胞凋亡减少。EP以浓度依赖的方式抑制32Dcl3细胞中辐射诱导的半胱天冬酶3激活和聚（ADP - 核糖）聚合酶（PARP）裂解。给接受9.75 Gy全身照射（TBI）的C57BL/6NHsd小鼠腹腔注射EP。这种治疗显著提高了生存率。无论EP治疗是在TBI前1小时开始并在TBI后连续5天持续进行，还是该化合物仅在TBI前1小时注射或仅在TBI后注射5天，生存益处都是明显的。在所有体外和体内实验中，EP的无活性类似物乳酸乙酯没有可检测到的辐射防护或减轻作用。EP可能是一种有效的辐射防护剂和TBI诱导的造血综合征减轻剂。
