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Updated: Jul 9, 2026
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Drug-induced liver graft toxicity caused by cytochrome P450 poor metabolism
László Kóbori1, Krisztina Kõhalmy, Pálma Porrogi
1Transplantation and Surgical Clinic, Semmelweis University, Baross 23-25, H-1082 Budapest, Hungary.
Unlabelled:
What is already known about this subject. The activity of drug-metabolizing enzymes, primarily cytochrome P450 enzymes, can determine a patient's response to a drug. Therapeutic failure or drug toxicity in the postoperative period after liver transplantation is influenced by the drug metabolizing capacity of the graft. Dose adjustment or selection of an alternative drug, which is not a substrate for the polymorphic enzyme may prevent the development of side-effects in recipients of poor metabolizer liver grafts. What this study adds. A validated analytical system with metabolomic tools has been developed to estimate the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates the improvement of individual recipient therapy. In the test of drug-metabolizing status, one of the liver grafts was found to be a CYP2C9 poor metabolizer, while the other was a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week.
Aims:
The drug-metabolizing capacity of transplanted liver highly influences drug efficacy or toxicity, particularly in the early postoperative period. The aim of our study was to predict therapeutic failures or severe adverse drug reactions by phenotyping for cytochrome P450 (P450) polymorphism resulting in reduced or no activity of the key drug-metabolizing enzymes.
Methods:
A validated analytical system with metabolomic tools has been developed for estimation of the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates improvement of the individual recipient therapy.
Results:
Of the 109 liver donors in Hungary, the frequency of poor metabolizers was found to be 0.92%, 5.5% and 8.3% for CYP2C9, CYP2C19 and CYP2D6, respectively. In the present study, two liver grafts transplanted in paediatric recipients were reported to be poor metabolizer phenotypes. The liver grafts presented normal function in the early postoperative days; 2 weeks after transplantation, however, increasing liver enzymes were detected. Histological investigation of a liver biopsy suggested drug toxicity. The test of drug metabolizing status showed one of the liver grafts to be a CYP2C9 poor metabolizer, and the other was found to be a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week.
Conclusions:
Prospective investigation of the P450 status may lead to the optimization of drug choice and/or dose for a more effective therapy, avoid serious adverse effects, and decrease medical costs. Phenotyping donor livers and tailored medication can contribute to the improvement of graft and recipient survival.
Insights
Assessing liver graft drug-metabolizing capacity using metabolomic tools predicts poor metabolizer phenotypes. This enables tailored medication, improving graft and recipient outcomes after liver transplantation.
Area of Science:
- Pharmacogenomics
- Transplantation medicine
- Drug metabolism
Background:
- Cytochrome P450 (P450) enzyme activity significantly impacts drug response and postoperative outcomes in liver transplant recipients.
- Reduced drug-metabolizing capacity of transplanted liver grafts can lead to therapeutic failure or toxicity.
- Identifying poor metabolizer phenotypes in donors is crucial for optimizing recipient therapy and preventing adverse events.
Purpose of the Study:
- To develop and validate an analytical system using metabolomic tools to estimate the drug-metabolizing capacity of transplanted livers.
- To predict potential poor metabolizer phenotypes in liver donors.
- To improve individual recipient therapy by identifying and managing drug metabolism variations.
Main Methods:
- Development of a validated analytical system incorporating metabolomic tools.
- Estimation of drug-metabolizing capacity in transplanted liver grafts.
- Phenotyping for cytochrome P450 (P450) polymorphism (CYP2C9, CYP2C19, CYP2D6).
Main Results:
- A validated analytical system was established for estimating liver graft drug-metabolizing capacity.
- Two pediatric liver recipients received grafts with poor metabolizer phenotypes (one CYP2C9, one CYP2C19).
- Medication rationalization led to graft and recipient recovery within one week.
Conclusions:
- Prospective phenotyping of P450 status in donor livers optimizes drug selection and dosage.
- Tailored medication based on donor liver P450 status improves graft and recipient survival.
- Early identification and management of poor metabolizer phenotypes reduce adverse drug reactions and healthcare costs.
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