# PXR-Mediated Xenobiotic Response in the Pathog  enesis Hemorrhagic Shock

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $352,125

## Abstract

Title: PXR-Mediated Xenobiotic Response in the Pathogenesis Hemorrhagic Shock
Project Summary/Abstract:
The goal of this proposal is to understand the role of xenobiotic receptor pregnane X receptor (PXR) in the
pathogenesis and clinical outcome of hemorrhagic shock (HS). HS is a life-threatening condition often
associated with traumatic injuries. Severe HS can lead to injury to multiple tissues, including the liver. In
addition to the liver injury, HS and the resulting tissue hypofusion also induce a cascade of inflammatory and
oxidative stress, leading to an overall suppression of drug metabolism in the liver. The HS-responsive
suppression of hepatic drug metabolism has potential clinical implications, because seriously injured trauma
patients are uniformly prescribed with multiple medications.
PXR is a master regulator of xenobiotic response through its transcriptional regulation of the phase I and
phase II drug-metabolizing enzymes (DMEs) and transporters, especially in the liver. In addition to inducing
cytochrome P450 (CYP) enzymes, another potential outcome of PXR activation is the increased production of
reactive oxygen species (ROS) as a result of increased CYP-mediated oxidations. Many of the drugs often
prescribed to the HS patients before or after the occurrence of trauma, such as RIF and DEX, are known PXR
activators and DME inducers in the liver. It has also been reported that the expression and activity of PXR
decreased in experimental HS. However, it is unclear whether PXR plays a role in the regulation of
hepatic drug metabolism in the setting of HS and if so, whether activation of PXR is beneficial or
detrimental to the HS-responsive liver injury.
Our preliminary results showed that: 1) Mice subjected to HS exhibit a dynamic regulation of PXR and hepatic
P450 enzymes, such as the Cyp3a11; 2) HS suppresses the metabolism of midazolam and Oxycodone, two
drugs commonly used in trauma care; 3) Genetic activation of PXR in transgenic mice sensitizes mice to HS-
responsive liver injury, but had little effect on HS-responsive lung injury; 4) The HS-responsive liver injury, but
not lung injury, was attenuated in Pxr-/- mice; 5) The sensitizing effect of the PXR transgene on HS-induced
liver injury is Cyp3a dependent; 6) The sensitizing effect of the PXR transgene on HS-responsive liver injury is
associated with increased hepatic oxidative stress; 7) The hPXR-hCYP3A4 humanized mice have been
created; and 8) Activation of constitutive androstane receptor (CAR) does not affect HS-responsive liver injury.
Based on these observations, we propose a reciprocal interaction between hemorrhagic shock (HS) and
hepatic drug metabolism or the regulation of hepatic drug metabolism. Specifically, we hypothesize
that 1) HS causes liver damage and has a dynamic effect on the expression of PXR, CYP3A and other
DMEs; and 2) Activation of PXR sensitizes HS-responsive liver injury by inducing the expression of
CYP3A and increasing oxidative stress. We propo...

## Key facts

- **NIH application ID:** 9849769
- **Project number:** 5R01DK117370-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Wen Xie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,125
- **Award type:** 5
- **Project period:** 2019-01-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849769

## Citation

> US National Institutes of Health, RePORTER application 9849769, PXR-Mediated Xenobiotic Response in the Pathog  enesis Hemorrhagic Shock (5R01DK117370-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9849769. Licensed CC0.

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