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Drug Metabolism and Disposition Fast Forward
First published on March 31, 2006; DOI: 10.1124/dmd.106.009662

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Received for publication February 6, 2006.
Revised March 24, 2006.
Accepted for publication March 28, 2006.

Regulation of CYP1A1 gene expression by the antioxidant tert-butylhydroquinone (tBHQ)

Thomas D Schreiber 1, Christoph Kohle 1, Felicitas Buckler 1, Stefan Schmohl 1, Albert Braeuning 1, Alexander Schmiechen 1, Michael Schwarz 1, Peter Munzel 2*

1 Institute of Pharmacology & Toxicology, University of Tuebingen 2 Institute of Pharmacology and Toxicology

* Address correspondence to: E-mail: peter.muenzel{at}uni-tuebingen.de

Abstract

Cytochrome P450 (CYP) 1A1, a major phase I enzyme, plays an important role in the metabolism of polycyclic aromatic hydrocarbons (PAH) and in the chemical activation of xenobiotics to carcinogenic derivatives. The phenolic antioxidant tert-butylhydroquinone (tBHQ), often used as a food preservative, is generally considered to act only as a monofunctional inducer of phase II enzymes thereby exerting chemoprotection. However, we recently observed that tBHQ elevated the activity of an aryl hydrocarbon receptor (AhR) response element (DRE)-driven luciferase reporter in human colon carcinoma cells Caco-2. We therefore studied the effects of tBHQ on the activity of a DRE-driven reporter, on CYP1A1 mRNA expression and CYP1A enzyme activity in Caco-2 cells and in human HepG2 hepatoma cells. tBHQ caused induction of reporter activity as well as CYP1A1 expression and activity in Caco-2 and HepG2 cells. Moreover, tBHQ combined with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased reporter activity and mRNA expression in Caco-2 cells in an additive manner. By contrast, tBHQ diminished TCDD-mediated induction of reporter activity and CYP1A1 mRNA expression in HepG2 cells. Resveratrol, an aryl hydrocarbon receptor (AhR) antagonist, repressed the induction of CYP1A1 by tBHQ. Cotransfection of HepG2 cells with a dominant negative Arnt mutant (aryl hydrocarbon receptor nuclear translocator) abolished the tBHQ-induced CYP1A1 reporter activity. These findings indicate that CYP1A1 may be induced by the antioxidant tBHQ via an AhR-dependent mechanism.


Key words: Ah receptor, antioxidants, ARNT, CYP induction, CYP1A, cytochrome P450 regulation


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