Pregnane X Receptor Activation in Liver Perfusion.

Abstract

BACKGROUND:

Liver normothermic machine perfusion (NMP) is being adopted as a method of optimizing livers before transplantation. However, there is further potential to use the NMP model as a platform for drug delivery. Pregnane X receptor (PXR) activation upregulates CYP3A expression and has been shown to be protective against ischemia-reperfusion in rodents. We introduced a PXR activator during NMP and assessed activation of its downstream targets.

METHODS AND MATERIALS:

Organs were perfused on a NMP circuit using an oxygenated red cell-based perfusate. A series of livers were allocated to PXR treatment and compared with a control group. Biopsies were taken at the start and end of the perfusion process to quantify CYP3A expression. Perfusion samples were taken throughout the perfusion process and used to measure biochemical variables (lactate and alanine transaminase).

RESULTS:

Quantification polymerase chain reaction using the delta computed tomography method on 5 livers which received Avasimibe demonstrated successful upregulation of CYP3A43 and CYP3A4 over the course of perfusion by 3.8-fold and 2.2-fold, respectively (P = .026 and P = .098, respectively; Student t test). The 4 control livers had no significant change in expression of CYP3A43 or CYP3A over the course of perfusion.

CONCLUSIONS:

We have demonstrated that NMP can be successfully used as a platform for drug delivery with reliable transcription activation of downstream targets. Although it remains to be seen whether PXR therapy is beneficial in humans, the model suggests that perfusion could be used clinically in the future to further optimize grafts by acting as a drug delivery system.

• Authors: Samuel Moulding, Rodrigo Figueiredo, Avinash Sewpaul, Alistair Leitch, Lucy Bates, Matthew Wright, Colin Wilson
• Journal: Transplantation proceedings (Transplant Proc) Vol. 54 Issue 3 Pg. 600-604 (Apr 2022) ISSN: 1873-2623 [Electronic] United States
• PMID: 35272879 (Publication Type: Journal Article)
• Copyright: Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.

Chemical References

• Pregnane X Receptor
• Cytochrome P-450 CYP3A

Topics

• Cold Ischemia
• Cytochrome P-450 CYP3A (genetics, metabolism)
• Humans
• Liver (pathology)
• Liver Transplantation (methods)
• Organ Preservation (methods)
• Perfusion (methods)
• Pregnane X Receptor (metabolism)
• Reperfusion Injury (pathology)