S-化减弱了孕妇X受体的过活和乙氨基诱导的肝损伤
Qi Cui1,2, Tingting Jiang1,2, Xinya Xie2
1Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
过量服用乙氨基会导致肝功能衰竭. 孕妇X受体 (PXR) 的S-化 (SNO) 通过减少PXR过活性来保护肝损伤,提供潜在的治疗标.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 分子毒理学 分子毒理学
- 药物新陈代谢 药物新陈代谢
背景情况:
- 药物诱导性肝损伤 (DILI),特别是来自乙氨基,是急性肝衰竭的主要原因.
- 孕妇X受体 (PXR) 调节药物代谢,其异常激活有助于乙氨基的肝毒性.
研究的目的:
- 为了研究S-化PXR (SNO-PXR) 作为对乙氨基暴露的反应.
- 阐明SNO-PXR在乙氨基引起的肝损伤中的作用.
主要方法:
- 在肝细胞和小鼠模型中,对乙氨基和S-尼特罗斯氨 (GSNO) 的暴露.
- 质谱学和位点定向的突变发生,以确定S-化位点.
- 评估PXR激活,肝损伤标志物 (例如,HMGB1) 和野生类型和PXR淘汰小鼠的炎症.
主要成果:
- 在对乙氨基或GSNO的反应中,PXR在氨酸307中经历S-化.
- 通过S-基化抑制了由激动剂和构成性活性形式的PXR激活.
- 降低PXR水平和增加的SNO-PXR在乙胺过量服用肝脏的中枢球区域中观察到.
- 在PXR-/-小鼠中,缺乏S-化酶的PXR加剧了肝损伤.
- 通过增加SNO-PXR水平,GSNOR抑制剂N6022证明了肝保护作用.
结论:
- 在对乙氨基的反应中,PXR通过S-基化进行翻译后修饰.
- 这种S-化修饰减轻了乙氨基诱导的PXR过活和随后的肝损伤.
- SNO-PXR代表了一种潜在的治疗点,用于控制乙氨基诱导的肝毒性.
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