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Molecular and Cellular Biology, October 1999, p. 6825-6832, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H2O2 and NFI

Yannick Morel,1 Nicolas Mermod,2 and Robert Barouki1,*

INSERM U490, Université Paris V-René Descartes, Centre Universitaire des Saints-Pères, 75006 Paris, France,1 and Laboratoire de Biotechnologie Moléculaire, Institut de Biologie Animale et Centre de Biotechnologie, UNIL-EPFL, Université de Lausanne, 1015 Lausanne, Switzerland2

Cytochrome P450 1A1 (CYP1A1), like many monooxygenases, can produce reactive oxygen species during its catalytic cycle. Apart from the well-characterized xenobiotic-elicited induction, the regulatory mechanisms involved in the control of the steady-state activity of CYP1A1 have not been elucidated. We show here that reactive oxygen species generated from the activity of CYP1A1 limit the levels of induced CYP1A1 mRNAs. The mechanism involves the repression of the CYP1A1 gene promoter activity in a negative-feedback autoregulatory loop. Indeed, increasing the CYP1A1 activity by transfecting CYP1A1 expression vectors into hepatoma cells elicited an oxidative stress and led to the repression of a reporter gene driven by the CYP1A1 gene promoter. This negative autoregulation is abolished by ellipticine (an inhibitor of CYP1A1) and by catalase (which catalyzes H2O2 catabolism), thus implying that H2O2 is an intermediate. Down-regulation is also abolished by the mutation of the proximal nuclear factor I (NFI) site in the promoter. The transactivating domain of NFI/CTF was found to act in synergy with the arylhydrocarbon receptor pathway during the induction of CYP1A1 by 2,3,7,8-tetrachloro-p-dibenzodioxin. Using an NFI/CTF-Gal4 fusion, we show that NFI/CTF transactivating function is decreased by a high activity of CYP1A1. This regulation is also abolished by catalase or ellipticine. Consistently, the transactivating function of NFI/CTF is repressed in cells treated with H2O2, a novel finding indicating that the transactivating domain of a transcription factor can be targeted by oxidative stress. In conclusion, an autoregulatory loop leads to the fine tuning of the CYP1A1 gene expression through the down-regulation of NFI activity by CYP1A1-based H2O2 production. This mechanism allows a limitation of the potentially toxic CYP1A1 activity within the cell.

* Corresponding author. Mailing address: INSERM U490, Université Paris V-René Descartes, Centre Universitaire des Saints-Pères, 45, rue des Saints-Pères, 75006 Paris, France. Phone: 33-1 42 86 20 75. Fax: 33-1 42 86 20 72. E-mail: robert.barouki{at}biomedicale.univ-paris5.fr.

Molecular and Cellular Biology, October 1999, p. 6825-6832, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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