Differential effects of a topoisomerase I inhibitor on dioxin inducibility and high-level expression of the cytochrome P450IA1 gene.

The basic helix-loop-helix containing dioxin receptor mediates dioxin signal transduction. The ligand-activated receptor complex binds to specific sequences termed xenobiotic response elements and regulates transcription of target genes such as the gene for cytochrome P450IA1. This study demonstrates that induction of cytochrome P450IA1 and P450IB1 gene expression by a dioxin receptor ligand is repressed by camptothecin, an inhibitor of the topoisomerase I enzyme. However, a transiently transfected reporter construct under control of an xenobiotic response element-containing promoter was not affected by the topoisomerase inhibitor. In agreement with this observation, ligand-dependent activation of the dioxin receptor to its DNA-binding form is not altered by camptothecin as analyzed by electrophoretic mobility shift assay. Moreover, the inhibitory effect of camptothecin cannot be exerted once the P450IA1 gene has been activated. These results imply that topoisomerase I activity is necessary for the primary P450IA1 induction response, possibly involving dioxin-dependent alterations in chromatin structure of the P450IA1 promoter.