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

0090-9556/06/3407-1096-1101$20.00
DMD 34:1096-1101, 2006

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REGULATION OF CYP1A1 GENE EXPRESSION BY THE ANTIOXIDANT TERT-BUTYLHYDROQUINONE

Thomas D. Schreiber1, Christoph Köhle1, Felicitas Buckler, Stefan Schmohl, Albert Braeuning, Alexander Schmiechen, Michael Schwarz, and Peter A. Münzel

Institute of Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Tübingen, Germany

CYP1A1, a major phase I enzyme, plays an important role in the metabolism of polycyclic aromatic hydrocarbons 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 mono-functional inducer of phase II enzymes, thereby exerting chemo-protection. 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). Therefore, we studied the effects of tBHQ on the activity of a DRE-driven reporter, CYP1A1 mRNA expression, and CYP1A enzyme activity in Caco-2 cells and human HepG2 hepatoma cells. We found tBHQ caused induction of reporter activity and 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 decreased TCDD-mediated induction of reporter activity and CYP1A1 mRNA expression in HepG2 cells. Resveratrol, an AhR antagonist, repressed the induction of CYP1A1 by tBHQ. Cotransfection of HepG2 cells with a dominant negative AhR nuclear translocator mutant abolished the tBHQ-induced CYP1A1 reporter activity. These findings indicate that CYP1A1 may be induced by the antioxidant tBHQ via an AhR-dependent mechanism.

Address correspondence to: Peter A. Münzel, Institute of Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Tübingen, Germany. E-mail: peter.muenzel{at}uni-tuebingen.de




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Drug Metab. Dispos., June 1, 2007; 35(6): 898 - 907.
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