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Published on: June 18, 2013
Pregnane X Receptor Activation in Liver Perfusion.
Samuel Moulding1, Rodrigo Figueiredo1, Avinash Sewpaul1
1Institute for Cellular Medicine, Faculty Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Cell and Molecular Biosciences, Faculty Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Normothermic machine perfusion (NMP) successfully delivered drugs to activate targets in the liver. This approach shows potential for optimizing organ grafts for transplantation in the future.
Area of Science:
- Organ transplantation
- Pharmacology
- Biochemistry
Background:
- Liver normothermic machine perfusion (NMP) is emerging for optimizing donor livers.
- NMP offers potential as a platform for targeted drug delivery.
- Pregnane X receptor (PXR) activation enhances CYP3A expression and offers protection against ischemia-reperfusion injury in rodent models.
Purpose of the Study:
- To investigate the use of NMP as a drug delivery platform.
- To assess the activation of PXR downstream targets during NMP.
Main Methods:
- Livers were perfused using an oxygenated, red cell-based perfusate in an NMP circuit.
- Livers were treated with a PXR activator (Avasimibe) or served as controls.
- Liver biopsies and perfusion samples were analyzed for CYP3A expression and biochemical markers.
Main Results:
- Avasimibe treatment during NMP significantly upregulated CYP3A43 (3.8-fold) and CYP3A4 (2.2-fold) expression.
- Control livers showed no significant changes in CYP3A expression.
- Biochemical variables were monitored throughout the perfusion process.
Conclusions:
- NMP serves as an effective platform for drug delivery, achieving reliable transcriptional activation of downstream targets.
- This perfusion model demonstrates potential for clinical application in optimizing organ grafts.
- Further research is needed to determine the clinical efficacy of PXR therapy in human liver transplantation.
