Repression of cytochrome P450 1A1 gene expression by oxidative stress: mechanisms and biological implications.

Cytochrome P450 1A1 (CYP1A1) is a member of a multigenic family of xenobiotic-metabolizing enzymes. Beyond its usual role in the detoxification of polycyclic aromatic compounds, the activity of this enzyme can be deleterious since it can generate mutagenic metabolites and oxidative stress. The CYP1A1 gene is highly inducible by the environmental contaminants dioxin and benzo[a]pyrene. We discuss here the regulatory mechanisms that limit this induction. Several feedback loops control the activation of this gene and the subsequent potential toxicity. The oxidative repression of the CYP1A1 gene seems to play a central role in these regulations. The transcription factor Nuclear Factor I/CCAAT Transcription Factor (NFI/CTF), which is important for the transactivation of the CYP1A1 gene promoter, is particularly sensitive to oxidative stress. A critical cysteine within the transactivating domain of NFI/CTF appears to be the target of H(2)O(2). The DNA-binding domains of several transcription factors have been described as targets of oxidative stress. However, recent studies described here suggest that more attention should be given to transactivating domains that may represent biologically relevant redox targets of cellular signaling.