In rat in vivo, both
paracetamol (
APAP) and
carbon tetrachloride (CCl4) induce liver
necrosis, but long-term treatment with CCl4, in contrast to
paracetamol, causes
liver fibrosis. The aim of this study was to perform transcriptomic analysis to compare the early changes in
mRNA expression profiles induced by
APAP and CCl4 in the rat precision-cut liver slice model (PCLS) and to identify early markers that could predict
fibrosis-inducing potential. Microarray data of rat PCLS exposed to
APAP andCCl4was generated using a toxic dose based on decrease in
ATP levels. Toxicity pathway analysis using a custom made
fibrosis-related gene list showed
fibrosis as one of the predominant toxic endpoints in CCl4-treated, but not in
APAP-treated PCLS. Moreover, genes which have a role in
fibrosis such as
alpha-B crystallin, jun proto-oncogene,
mitogen-activated protein kinase 6,
serpin peptidase inhibitor and also the
transcription factor Kruppel-like-factor-6 were up-regulated by CCl4, but not by
APAP. Predicted activation or inhibition of several upstream regulators due to CCl4 is in accordance with their role in
fibrosis. In conclusion, transcriptomic analysis of PCLS successfully identified the fibrotic potential of CCl4 as opposed to
APAP. The application of PCLS as an ex vivo model to identify early
biomarkers to predict the fibrogenic potential of toxic compounds should be further explored.