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Detection of early signals of hepatotoxicity by gene expression profiling studies with cultures of metabolically competent human hepatocytes

: Thum, T.; Borlak, J.


Archives of toxicology 82 (2008), Nr.2, S.89-101
ISSN: 0340-5761
ISSN: 1432-0738
Fraunhofer ITEM ()
hepatotoxicity; toxicogenomics; gene expression; gene expression profiling

Xenobiotic induced liver injury is a leading cause for drug withdrawal and toxicogenomics may help to identify molecular causes.
Here we report studies with cultures of human hepatocytes to detect early responses of liver toxicity upon treatment with the hepatotoxin Aroclor 1254. We studied transcript abundance of 302 genes with biological functions in detoxification, cell proliferation, tumor development, stress response, signal transduction, apoptosis and cell cycle regulation. More than 40 genes were regulated by at least twofold change, the majority coding for xenobiotic defense. In the case of CYP monooxygenases induction of coded protein was confirmed by Western immunoblotting whereas catalytic activities were determined by assaying for testosterone hydroxylase activity.
There was good agreement between gene and protein expression and enzyme activity of CYP monooxygenases. In conclusion, xenobiotic induced hepatotoxicity may arise via several mechanisms and gene expression profiling helps to pinpoint location and pathways perturbed by drugs and chemicals.