DNA Damage Response Regulates Initiation of Liver Regeneration Following Acetaminophen Overdose.
DNA Damage Response Regulates Initiation of Liver Regeneration Following Acetaminophen Overdose.
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DOI：
10.3727/105221618x15205260749346
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发表时间：
2018-05-18
期刊：
影响因子：
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通讯作者：
Apte U
中科院分区：
文献类型：
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作者：
Borude P;Bhushan B;Apte U
对乙酰氨基酚（APAP）过量是急性肝衰竭（ALF）的主要原因，治疗选择有限。已知APAP诱导ALF后的肝再生是最终结果的决定性因素。我们实验室先前的研究使用增量剂量模型，涉及小鼠中再生（300 mg/kg，APAP 300）和非再生（600 mg/kg，APAP 600）剂量的APAP，揭示了APAP过量后调节再生的几种促再生途径。在这里，我们报告DNA损伤和修复机制调节启动肝再生后APAP过量。用非再生APAP 600剂量处理的小鼠显示出比APAP 300更长的pH 2AX（DNA双链断裂（DSB）的标志物）表达。在再生APAP 300剂量处理的小鼠中，H2 AX在Tyr 142处快速去磷酸化，表明及时的DNA修复。APAP 600中几种DNA修复蛋白的表达显著降低。与APAP 600组相比，APAP 300组中参与DNA修复的聚（ADP）核糖聚合酶（PARP）活化显著更高。主要细胞周期检查点蛋白p53的激活在APAP 600中显著更高，这通过其靶基因的显著更高表达来证明。综上所述，这些数据表明，在高剂量APAP毒性中发生大量DNA双重损伤，并且在APAP过量后缺乏及时的DSB修复导致长时间的生长停滞、增殖性衰老，从而导致抑制的肝再生。
Acetaminophen (APAP) overdose is the leading cause of Acute Liver Failure (ALF) with limited treatment options. It is known that liver regeneration following APAP induced ALF is a deciding factor in the final outcome. Previous studies from our laboratory using incremental dose model involving a regenerating (300 mg/kg, APAP300) and a non-regenerating (600 mg/kg, APAP600) dose of APAP in mice have revealed several pro- regenerative pathways that regulate regeneration after APAP overdose. Here we report that DNA damage and repair mechanisms regulate initiation liver regeneration following APAP overdose. Mice treated with non-regenerating APAP600 dose showed prolonged expression of pH2AX, a marker of the DNA double strand break (DSB) than APAP300. In regenerating APAP300 dose treated mice H2AX was rapidly dephosphorylated at Tyr142 indicating timely DNA repair. Expression of several DNA repair proteins was substantially lower in APAP600. Poly (ADP) ribose polymerase (PARP) activation, involved in DNA repair, was significantly higher in APAP300 group compared to APAP600 group. Activation of p53, the major cell cycle checkpoint protein, was significantly higher in APAP600 as demonstrated by substantially higher expression of its target genes. Taken together, these data show that massive DNA double damage occurs in high dose APAP toxicity and lack of prompt DSB repair after APAP overdose leads to prolonged growth arrest, proliferative senescence resulting in inhibited liver regeneration.