Accumulation of the Nuclear Dioxin (Ah) Receptor and Transcriptional Activation of the Mouse Cyp1a-1 and Cyp1a-2 Genes

The treatment of C57BL/6 mice with 2,3,7,8-tetra-chlorodibenzo- p-dioxin (TCDD) leads to the nuclear uptake of the arylhydrocarbon receptor (AhR) and transcriptional activation of Cyp1a1 and Cyp1a-2 (S. T. Okino, et al., J. Biol. Chem. 267, 6991, 1992). In the present study, early nuclear uptake of the AhR and its role in transcriptional activation of the Cyp1 genes have been evaluated. After 30 mm following a dose of TCDD to C57BL/6 mice, the AhR could be detected in liver nuclei. The effect of TCDD treatment within 30 min enhanced the transcriptional rate of the Cyp1a-2 gene to 70% of its maximal rate, with maximal levels of transcription occurring after 1 h. Early increases in 1a-2 mRNA were also observed by 30 min and increased to maximal levels by 12 h. In contrast, the levels of Cyp1a-1 transcription were 5 to 10% of maximal levels at 30 min, and gradually increased to maximal levels by 2 h. Concordant with the levels of transcription, 1a-1 mRNA was not detected until 1 h following TCDD treatment. While the AhR is responsible for transcriptional activation of the Cyp1a-1 gene, the concordant increase in the nuclear accumulation of the ligand-dependent AhR and Cyp1a-2 gene transcription suggests that the receptor plays an important role in the regulation of the Cyp1a-2 gene.