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-tetrachlorodibenzo-p-dioxin (TCDD) leads to the nuclear uptake of the arylhydrocarbon receptor (AhR) and transcriptional activation of Cyp1a-1 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 min 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.
Pendurthi
U R
UR
Department of Pharmacology, UCSD Cancer Center, San Diego, La Jolla 92093.
Okino
S T
ST
Tukey
R H
RH
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009685:Nuclear Envelope / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D017931:DNA Primers; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System