Detection of early signals of hepatotoxicity by gene expression profiling studies with cultures of metabolically competent human hepatocytes.
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.
Thum
Thomas
T
Fraunhofer Institute of Toxicology and Experimental Medicine, Centre for Drug Research and Medical Biotechnology, Nikolai-Fuchs-Str.1, 30625, Hannover, Germany.
Borlak
Jürgen
J
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020111:Chlorodiphenyl (54% Chlorine) / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System