Down-regulation of cytochrome P450 1A1 gene promoter by oxidative stress. Critical contribution of nuclear factor 1.
Oxidative stress interferes with several cellular functions, in particular transcriptional regulation. We show here that the human cytochrome P450 1A1 (CYP1A1) is down-regulated at the transcriptional level by oxidative stress. Basal as well as 2,3,7, 8-tetrachloro-p-dioxin-induced promoter activities are strongly impaired by H2O2 treatment or glutathione depletion with L-buthionine-(S,R)-sulfoximine. Tumor necrosis factor alpha inhibits CYP1A1 expression, and this inhibition is prevented by the antioxidant pyrrolidine dithiocarbamate. We show that these regulations depend on the integrity of the nuclear factor 1 (NFI) site located in the proximal promoter. We therefore examined the redox regulation of this transcription factor. Treatment of human HepG2 or rat H4 hepatoma cells with H2O2 or L-buthionine-(S, R)-sulfoximine inactivates the binding of the NFI transcription factor to its DNA consensus sequence. Furthermore, H2O2 treatment leads to a dose-dependent decrease of reporter gene expressions driven by promoters containing NFI binding sites. Glutathione depletion and catalase inhibition also repress a NFI-driven promoter. Under the same conditions, the CP-1 transcription factor activity is not affected by oxidative stress. Thus, NFI seems particularly sensitive to oxidative stress. This accounts, at least partially, for the regulation of cyp1A1 gene expression.
Morel
Y
Y
INSERM U490, Centre Universitaire des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris, France.
Barouki
R
R
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D018384:Oxidative Stress; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1
D000975:Antioxidants; D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D000072317:Polychlorinated Dibenzodioxins; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D006861:Hydrogen Peroxide; D019363:Cytochrome P-450 CYP1A1; D005978:Glutathione