title: Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes.
abstract: 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 24h of incubation and represent a valuable model for human in vitro hepatotoxicity testing despite the human inter-individual variability.
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands. m.g.l.elferink@rug.nl
authors.forename: M G L
authors.initials: MG
authors.lastname: Elferink
authors.forename: P
authors.initials: P
authors.lastname: Olinga
authors.forename: E M
authors.initials: EM
authors.lastname: van Leeuwen
authors.forename: S
authors.initials: S
authors.lastname: Bauerschmidt
authors.forename: J
authors.initials: J
authors.lastname: Polman
authors.forename: W G
authors.initials: WG
authors.lastname: Schoonen
authors.forename: S H
authors.initials: SH
authors.lastname: Heisterkamp
authors.forename: G M M
authors.initials: GM
authors.lastname: Groothuis
mesh_terms: D000293:Adolescent; D002648:Child; D055808:Drug Discovery; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D025341:Principal Component Analysis / Q000379:methods; D013312:Stress, Physiological / Q000235:genetics; D043922:Toxicogenetics / Q000379:methods; D055815:Young Adult