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 cu 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.