Induction of nuclear transcription factors, cytochrome P450 monooxygenases, and glutathione S-transferase alpha gene expression in Aroclor 1254-treated rat hepatocyte cultures.
Aroclor 1254 is a complex mixture of polychlorinated biphenyls and is well known for its potency to induce drug-metabolising enzymes, but little is known about its ability to modulate gene expression of transcription factors, which code for proteins that bind to the regulatory elements of DNA and facilitate transcriptional activation. We therefore investigated the gene expression of the liver-specific transcription factors CCAAT/enhancer-binding protein alpha (c/EBPalpha), hepatic nuclear factor (HNF) 1 and 4, and major cytochrome P450 (CYP) isozymes in addition to glutathione S-transferase alpha 2 (GSTA-2) in cultures of primary rat hepatocytes. We found highly significant and dose-dependent increases of c/EBPalpha (up to 62-fold), HNF-1 (up to 7-fold), HNF-4 (up to 8-fold), and 50- and 4-fold inductions of GSTA-2 and CYP monooxygenases, respectively. Based on the ethoxyresorufin-O-deethylase assay, the gene expression and enzyme activity for CYP1A1 were in good agreement, but for other CYP isozymes similar correlations could not be obtained. In conclusion, the simultaneous induction of liver-specific TFs and of several detoxifying enzymes may point to a coordinate genomic response in cultures of rat hepatocytes upon treatment with Aroclor 1254.
Borlak
J
J
Fraunhofer Institute of Toxicology and Aerosol Research, Department of Molecular Toxicology and Pharmacokinetics, Hannover, Germany. Borlak@ita.fhg.de
Thum
T
T
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D002478:Cells, Cultured; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D013956:Antithyroid Agents; D007527:Isoenzymes; D014157:Transcription Factors; D020111:Chlorodiphenyl (54% Chlorine); D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha