Evidence for a new human CYP1A1 regulation pathway involving PPAR-? and 2 PPRE sites
E. Sérée, P.-H. Villard, J.-M. Pascussi, T. Pineau, P. Maurel, Q.B. Nguyen, F. Fallone, P.-M. Martin, S. Champion, B. Lacarelle, J.-F. Savouret, Y. Barra
Background & Aims: Cytochrome P450 1A1 catalyzes the degradation of endobiotics (estradiol, fatty acids, and so on) and the bioactivation of numerous environmental procarcinogens, such as arylamines and polycyclic aromatic hydrocarbons, that are found in food. Several peroxisome proliferators and arachidonic acid derivatives enhance cytochrome P450 1A1 activity, but the mechanisms involved remain unknown. The aim of this work was to study the role of peroxisome proliferatoractivated receptors in cytochrome P450 1A1 gene induction. Methods: The role of peroxisome proliferatoractivated receptor transcription factors in cytochrome P450 1A1 induction was assessed by means of enzymatic activities, quantitative real-time polymerase chain reaction, gene reporter assays, mutagenesis, and electrophoretic mobility shift assay. Results: We show that peroxisome proliferatoractivated receptor-? agonists (WY-14643, bezafibrate, clofibrate, and phthalate) induce human cytochrome P450 1A1 gene expression, whereas 2,4-thiazolidinedione, a specific peroxisome proliferatoractivated receptor-? agonist, represses it. The induction of cytochrome P450 1A1 transcripts by WY-14643 was associated with a marked increase of ethoxyresorufin O-deethylase activity (10-fold at 200 ?mol/L). Transfection of peroxisome proliferatoractivated receptor-? complementary DNA enhanced cytochrome P450 1A1 messenger RNA induction by WY-14643, although WY-14643 failed to activate xenobiotic responsive element sequences. Two peroxisome proliferator response element sites were located at positions ?931/?919 and ?531/?519 of the cytochrome P450 1A1 promoter. Their inactivation by directed mutagenesis suppressed the inductive effect of WY-14643 on cytochrome P450 1A1 promoter activation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay experiments showed that the 2 cytochrome P450 1A1 peroxisome proliferator response element sites bind the peroxisome proliferatoractivated receptor-?/retinoid X receptor-? heterodimer. Conclusions: We describe here a new cytochrome P450 1A1 induction pathway involving peroxisome proliferatoractivated receptor-? and 2 peroxisome proliferator response element sites, indicating that peroxisome proliferatoractivated receptor-? ligands, which are common environmental compounds, may be involved in carcinogenesis.
© 2004 by the American Gastroenterological Association
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