Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock Induced Liver Injury

Abstract

Hemorrhagic shock (HS) is a life‐threatening condition often associated with traumatic injuries. Hemorrhagic shock causes tissue hypoperfusion, which may lead to injury to multiple organs including the liver. Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the expression of drug‐metabolizing enzymes (DMEs) such as CYP3A. Many of the drugs used in the trauma patients are known to activate PXR and induce CYP3A. However, it is unclear whether and how PXR plays a role in the regulation of DMEs in the setting of HS and if so, whether activation of PXR beneficial or detrimental to the HS‐responsive liver injury. In this study, we showed that genetic or pharmacological activation of PXR sensitized mice to HS‐responsive liver injury, whereas ablation of PXR protected liver from damage following HS. Mechanistically, the sensitizing effect of PXR activation may have been accounted for by the PXR‐responsive induction of Cyp3a and increased oxidative stress in the liver. Pharmacological inhibition of Cyp3a attenuated the sensitizing effect of PXR. Treatment with the antioxidant NACA relieved the oxidative stress and protected mice from HS‐responsive liver injury. Our results suggest that the unavoidable use of PXR‐activating drugs in trauma patients has the potential to exacerbate HS‐responsive liver injury, which can be mitigated by the co‐administration of anti‐oxidative agents.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.