Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes

Journal Article · Sun May 15 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.03.010· OSTI ID:21535299

Elferink, M G.L., ^[1]; Olinga, P ^[1]; van Leeuwen, E M; Bauerschmidt, S; Polman, J ^[2]; Schoonen, W G ^[3]; Heisterkamp, S H ^[4]; Groothuis, G M.M. ^[1]

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1. Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen (Netherlands)
2. Molecular Design and Informatics, MSD, Oss (Netherlands)
3. Toxicology and Drug Disposition, MSD, Oss (Netherlands)
4. Biostatistics and Research Decision Sciences MSD, Oss (Netherlands)

In the process of drug development it is of high importance to test the safety of new drugs with predictive value for human toxicity. A promising approach of toxicity testing is based on shifts in gene expression profiling of the liver. Toxicity screening based on animal liver cells cannot be directly extrapolated to humans due to species differences. The aim of this study was to evaluate precision-cut human liver slices as in vitro method for the prediction of human specific toxicity by toxicogenomics. The liver slices contain all cell types of the liver in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process. Previously we showed that toxicogenomic analysis of rat liver slices is highly predictive for rat in vivo toxicity. In this study we investigated the levels of gene expression during incubation up to 24 h with Affymetrix microarray technology. The analysis was focused on a broad spectrum of genes related to stress and toxicity, and on genes encoding for phase-I, -II and -III metabolizing enzymes and transporters. Observed changes in gene expression were associated with cytoskeleton remodeling, extracellular matrix and cell adhesion, but for the ADME-Tox related genes only minor changes were observed. PCA analysis showed that changes in gene expression were not associated with age, sex or source of the human livers. Slices treated with acetaminophen showed patterns of gene expression related to its toxicity. These results indicate that precision-cut human liver slices are relatively stable during 24 h of incubation and represent a valuable model for human in vitro hepatotoxicity testing despite the human inter-individual variability.

• OSTI ID: 21535299
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 253; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACCURACY
ADHESION
ANIMAL CELLS
ANIMALS
BIOTECHNOLOGY
BODY
CELL CONSTITUENTS
DIGESTIVE SYSTEM
DRUGS
ENZYMES
FORECASTING
GENES
GLANDS
HUMAN POPULATIONS
IN VITRO
IN VIVO
INCUBATION
LIVER
LIVER CELLS
MAMMALS
MICROARRAY TECHNOLOGY
MICROTUBULES
ORGANIC COMPOUNDS
ORGANS
POPULATIONS
PROTEINS
RATS
RODENTS
SAFETY
SOMATIC CELLS
TESTING
TOXICITY
VERTEBRATES