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Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days.

Abstract：

:Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and function of hPCLS to 5 days of incubation. hPCLS were incubated in two media developed for long-term culture of hepatocytes, RegeneMed®, and Cellartis®, and in the standard medium WME. Maintenance of phase I and II metabolism was studied both on gene expression as well as functional level using a mixture of CYP isoform-specific substrates. Albumin synthesis, morphological integrity, and glycogen storage was assessed, and gene expression was studied by transcriptomic analysis using microarrays with a focus on genes involved in drug metabolism, transport and toxicity. The data show that hPCLS retain their viability and functionality during 5 days of incubation in Cellartis® medium. Albumin synthesis as well as the activity and gene expression of phase I and II metabolic enzymes did not decline during 120-h incubation in Cellartis® medium, with CYP2C9 activity as the only exception. Glycogen storage and morphological integrity were maintained. Moreover, gene expression changes in hPCLS during incubation were limited and mostly related to cytoskeleton remodeling, fibrosis, and moderate oxidative stress. The expression of genes involved in drug transport, which is an important factor in determining the intracellular xenobiotic exposure, was also unchanged. Therefore, we conclude that hPCLS cultured in Cellartis® medium are a valuable human ex vivo model for toxicological and pharmacological studies that require prolonged xenobiotic exposure.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Starokozhko V,Vatakuti S,Schievink B,Merema MT,Asplund A,Synnergren J,Aspegren A,Groothuis GMM

doi

10.1007/s00204-016-1865-x

subject

Has Abstract

pub_date

2017-05-01 00:00:00

pages

2079-2092

issue

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-016-1865-x

journal_volume

pub_type

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Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days.