Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage.

Thomas Schreiter,Robert K Gieseler,Ali Canbay,Karl-Heinz Strucksberg,Hideo A Baba,Guido Gerken,Andreas Paul,Margarete Odenthal,Jürgen Treckmann,Martin Schlattjan,Gavin E Arteel,Jan-Peter Sowa

doi:10.1038/srep31916

Thomas Schreiter, Robert K Gieseler + Show 10 more

Open Access

https://doi.org/10.1038/srep31916

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Abstract

Reliable test systems to identify hepatotoxicity are essential to predict unexpected drug-related liver injury. Here we present a human ex-vivo liver model to investigate acetaminophen-induced liver injury. Human liver tissue was perfused over a 30 hour period with hourly sampling from the perfusate for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers. In addition, the release of microRNA-122 was significantly higher in acetaminophen-treated than in non-treated livers. Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in patients.

Highlights

Potential hepatotoxicity is a key issue in newly developed, repurposed and approved drugs
Within the hepatocyte a small amount of APAP is metabolized to N-Acetyl-p-benzochinonimin (NAPQI) by cytochrome P450 isoenzyme 2E1 (CYP2E1)
Liver function and general metabolism is diminished by APAP poisoning

Summary

Introduction

Potential hepatotoxicity is a key issue in newly developed, repurposed and approved drugs. Drug-induced liver injury (DILI) has mostly been investigated in animal models or specialized cell culture systems. These often fail to reflect all relevant metabolic processes in the human in-vivo setting[1]. Reliable ex-vivo systems of functionally intact human liver tissue promise to avoid such shortcomings and may even outperform the informative value of animal models. Such systems might be able to complement animal toxicity studies prior submitting a clinical trial application. In this study perfused liver sections were treated with acetaminophen to establish a possible use of the perfusion system as model for DILI and to identify hepatotoxicity

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