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 kn own about its ability to modulate gene expression of transcription factors, which code for proteins that bind to the regulatory elements of DNA and fa cilitate transcriptional activation. We therefore investigated the gene exp ression of the liver-specific transcription factors CCAAT/enhancer-binding protein alpha (c/EBP alpha), hepatic nuclear factor (HNF) 1 and 4, and majo r cytochrome P450 (CYP) isozymes in addition to glutathione S-transferase a lpha 2 (GSTA-2) in cultures of primary rat hepatocytes. We found highly sig nificant and dose-dependent increases of c/EBP alpha (up to 62-fold), HNF-1 (up to 7-fold), HNF-4 (up to 8-fold), and 50- and 4-fold inductions of GST A-2 and CYP monooxygenases, respectively. Based on the ethoxyresorufin-O-de ethylase assay, the gene expression and enzyme activity for CYP1A1 were in good agreement, but for other CYP isozymes similar correlations could not b e obtained. In conclusion, the simultaneous induction of liver-specific TFs and of several detoxifying enzymes may point to a coordinate genomic respo nse in cultures of rat hepatocytes upon treatment with Aroclor 1254. (C) 20 01 Elsevier Science Inc. All rights reserved.