Vol. 57, Issue 6, 1158-1164, June 2000

A Repressive Cross-Regulation between Catalytic and Promoter Activities of the CYP1A1 and CYP2E1 Genes: Role of H₂O₂

Yannick Morel, Isabelle de Waziers, and Robert Barouki

Institut National de la Santé et de la Recherche Médicale U490, Université Paris V-René Descartes, Centre Universitaire des Saints-Pères, Paris, France

Cytochrome P450 enzymes catalyze the first step of the metabolism and subsequent elimination of hydrophobic xenobiotics. However, the activity of some isoforms, among them CYP1A1 and CYP2E1, may result in cellular insults such as oxidative stress and activation of procarcinogen compounds into reactive metabolites. The regulation of the expression of these enzymes is therefore important. We have previously shown that the CYP1A1 gene promoter was repressed by oxidative stress. We show here that the CYP2E1 gene promoter is down-regulated by exogenous H₂O₂ addition and glutathione depletion. It is also repressed by the transfection of a CYP2E1 expression vector, which elicits an intracellular H₂O₂ generation. This autoregulation is limited by catalase (which catalyzes the catabolism of H₂O₂), thus implying H₂O₂ as a mediator of the negative feedback mechanism. Furthermore, we observed that the activity of CYP1A1 resulting either from the stimulation of the endogenous gene by benzo[a]pyrene treatment or from the transfection of an expression vector, repressed the activity of the CYP2E1 gene promoter. Conversely, CYP2E1 overexpression repressed the activity of the CYP1A1 gene promoter. In both cases, catalase and a specific inhibitor of one enzyme prevented the repression of the other. This suggests that the generation of H₂O₂ during the catalytic cycle of these enzymes is a mediator of the cross-regulatory mechanisms. These novel repressive mechanisms of autoregulation and cross-regulation using H₂O₂ as a common mediator may limit the potential toxicity resulting from high cytochrome P450 activity within the cell.