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J. Biol. Chem., Vol. 276, Issue 7, 4819-4827, February 16, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/7/4819    most recent M008495200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mathieu, M.-C. Articles by Raymond, M. Search for Related Content PubMed PubMed Citation Articles by Mathieu, M.-C. Articles by Raymond, M.

Aromatic Hydrocarbon Receptor (AhR)·AhR Nuclear Translocator- and p53-mediated Induction of the Murine Multidrug Resistance mdr1 Gene by 3-Methylcholanthrene and Benzo(a)pyrene in Hepatoma Cells^*

Marie-Claude Mathieu, Isabelle Lapierre, Karine Brault, and Martine Raymond^§

From the Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada

The mouse multidrug resistance gene family consists of three genes (mdr1, mdr2, and mdr3) encoding P-glycoprotein. We show that the expression of mdr1 is increased at the transcriptional level upon treatment of the hepatoma cell line Hepa-1c1c7 with the polycyclic aromatic hydrocarbon 3-methylcholanthrene (3-MC). This increase is not observed in the aromatic hydrocarbon receptor (AhR)-defective TAOc1BP^rc1 and the AhR nuclear translocator (Arnt)-defective BP^rc1 variants, demonstrating that the induction of mdr1 by 3-MC requires AhR·Arnt. We show that the mdr1 promoter (1165 to +84) is able to activate the expression of a reporter gene in response to 3-MC in Hepa-1c1c7 but not in BP^rc1 cells. Deletion analysis indicated that the region from 245 to 141 contains cis-acting sequences mediating the induction, including a potential p53 binding sequence. 3-MC treatment of the cells increased the levels of p53 and induced p53 binding to the mdr1 promoter in an AhR·Arnt-dependent manner. Mutations in the p53 binding site abrogated induction of mdr1 by 3-MC, indicating that p53 binding to the mdr1 promoter is essential for the induction. Benzo(a)pyrene, a polycyclic aromatic hydrocarbon and AhR ligand, which, like 3-MC, is oxidized by metabolizing enzymes regulated by AhR·Arnt, also activated p53 and induced mdr1 transcription. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, an AhR ligand resistant to metabolic breakdown, had no effect. These results indicate that the transcriptional induction of mdr1 by 3-MC and benzo(a)pyrene is directly mediated by p53 but that the metabolic activation of these compounds into reactive species is necessary to trigger p53 activation. The ability of the anticancer drug and potent genotoxic agent daunorubicin to induce mdr1 independently of AhR·Arnt further supports the proposition that mdr1 is transcriptionally up-regulated by p53 in response to DNA damage.

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