Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock–Induced Liver Injury
Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock–Induced Liver Injury
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DOI：
10.1002/hep.30691
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发表时间：
2019-06
期刊：
影响因子：
13.5
通讯作者：
Yang Xie;Meishu Xu;M. Deng;Zhigang Li;Pengcheng Wang;Songrong Ren;Yan Guo;Xiaochao Ma;Jie Fan;T. Billiar;W. Xie
中科院分区：
文献类型：
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作者：
Yang Xie;Meishu Xu;M. Deng;Zhigang Li;Pengcheng Wang;Songrong Ren;Yan Guo;Xiaochao Ma;Jie Fan;T. Billiar;W. Xie
出血性休克（HS）是一种与组织灌注不足相关的危及生命的疾病，通常会导致包括肝脏在内的多个器官损伤。孕烷X受体（PXR）是一种物种特异性的外源性受体，可调节药物代谢酶（DME）如细胞色素P450（CYP）3A的表达。许多临床药物，包括那些经常开给创伤患者，已知激活PXR和诱导CYP 3A。本研究的目的是确定PXR是否在HS背景下调节DME中发挥作用，以及PXR的激活对HS诱导的肝损伤是有益还是有害。对PXR转基因、基因敲除和人源化小鼠进行HS，并从组织学和生物化学上评估肝损伤。对PXR和CYP 3A的表达和/或活性进行遗传或非遗传操作，以确定其对HS诱导的肝损伤的影响。我们的结果表明，PXR的遗传或药理学激活使野生型和hPXR/CYP 3A 4人源化小鼠对HS诱导的肝损伤敏感，而PXR敲除保护小鼠免受HS诱导的肝损伤。从机制上讲，PXR激活的致敏作用是通过PXR应答性诱导CYP 3A和肝脏中氧化应激增加来解释的。通过清除或药理学抑制CYP 3A、抗氧化剂N-乙酰半胱氨酸酰胺治疗或PXR拮抗剂治疗，可减弱PXR的致敏作用。结论：我们已经揭示了PXR在HS诱导的肝损伤中的作用。我们的研究结果表明，创伤患者不可避免地使用PXR激活药物有可能加重HS诱导的肝损伤，这可以通过联合使用抗氧化剂，CYP 3A抑制剂或PXR拮抗剂来减轻。
Hemorrhagic shock (HS) is a life‐threatening condition associated with tissue hypoperfusion and often leads to injury of multiple organs including the liver. Pregnane X receptor (PXR) is a species‐specific xenobiotic receptor that regulates the expression of drug‐metabolizing enzymes (DMEs) such as the cytochrome P450 (CYP) 3A. Many clinical drugs, including those often prescribed to trauma patients, are known to activate PXR and induce CYP3A. The goal of this study is to determine whether PXR plays a role in the regulation of DMEs in the setting of HS and whether activation of PXR is beneficial or detrimental to HS‐induced hepatic injury. PXR transgenic, knockout, and humanized mice were subject to HS, and the liver injury was assessed histologically and biochemically. The expression and/or activity of PXR and CYP3A were manipulated genetically or pharmacologically in order to determine their effects on HS‐induced liver injury. Our results showed that genetic or pharmacological activation of PXR sensitized wild‐type and hPXR/CYP3A4 humanized mice to HS‐induced hepatic injury, whereas knockout of PXR protected mice from HS‐induced liver injury. Mechanistically, the sensitizing effect of PXR activation was accounted for by PXR‐responsive induction of CYP3A and increased oxidative stress in the liver. The sensitizing effect of PXR was attenuated by ablation or pharmacological inhibition of CYP3A, treatment with the antioxidant N‐acetylcysteine amide, or treatment with a PXR antagonist. Conclusion: We have uncovered a function of PXR in HS‐induced hepatic injury. Our results suggest that the unavoidable use of PXR‐activating drugs in trauma patients has the potential to exacerbate HS‐induced hepatic injury, which can be mitigated by the coadministration of antioxidative agents, CYP3A inhibitors, or PXR antagonists.