Background

Acetaminophen (APAP) overdose can cause severe acute liver injury. Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear protease that senses DNA breaks and repairs damaged DNA. The role PARP1 plays in APAP-induced hepatotoxicity is still unclear.

Materials and methods

The study was designed in two parts. First, the relationship between PARP1 expression and hepatotoxicity was investigated. Then, the inhibitor PJ34 was used to inhibit the activity of PARP1 and examined its effects. In particular, APAP, vehicle or PJ34 was intraperitoneally administered to mice. Serum transaminase levels were measured with commercial kits. Hematoxylin & eosin staining was used for histopathological observation of the liver. The protein levels of PARP1, poly (ADP-ribose), Sirtuin1 (Sirt1) and γ-H2AX were detected by western blotting.

Results

In a dose- and time-dependent manner, APAP exposure resulted in the overactivation of PARP1 in the livers of mice. Posttreatment with PJ34 ameliorated changes in serum transaminase levels, and histopathological abnormalities. The protein expression of Sirt1 was elevated by PJ34, while that of PARP1, poly (ADP-ribose), and γ-H2AX was reduced due to PJ34 administration.

Conclusion

Excessive APAP administration results in PARP1 overactivation, and its inhibition sheds light on the treatment of APAP-induced liver injury.

中文翻译：

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抑制聚（ADP-核糖）聚合酶 1 激活可减轻对乙酰氨基酚诱导的小鼠急性肝损伤

背景

对乙酰氨基酚（APAP）过量可导致严重的急性肝损伤。聚 (ADP-核糖) 聚合酶 1 (PARP1) 是一种核蛋白酶，可感知 DNA 断裂并修复受损的 DNA。PARP1 在 APAP 诱导的肝毒性中所起的作用尚不清楚。

材料和方法

该研究分为两部分。首先，研究了PARP1表达与肝毒性之间的关系。然后，使用抑制剂PJ34抑制PARP1的活性并检查其效果。具体地，将APAP、媒介物或PJ34腹膜内施用给小鼠。使用商业试剂盒测量血清转氨酶水平。苏木精和伊红染色用于肝脏的组织病理学观察。通过蛋白质印迹法检测PARP1、聚(ADP-核糖)、Sirtuin1(Sirt1)和γ-H2AX的蛋白水平。

结果

以剂量和时间依赖性方式，APAP 暴露导致小鼠肝脏中 PARP1 过度激活。PJ34 治疗后改善了血清转氨酶水平的变化和组织病理学异常。PJ34 升高了 Sirt1 的蛋白表达，而 PJ34 施用则降低了 PARP1、聚（ADP-核糖）和 γ-H2AX 的蛋白表达。

结论

过量的 APAP 给药会导致 PARP1 过度激活，其抑制作用为治疗 APAP 引起的肝损伤提供了线索。