Abstract
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.
Footnotes
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This work was supported by the Deutsche Forschungsgemeinschaft (DFG).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.009662.
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ABBREVIATIONS: PAH, polycyclic aromatic hydrocarbon; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; AhR, aryl hydrocarbon receptor; Arnt, aryl hydrocarbon receptor nuclear translocator; DRE, dioxin response element; tBHQ, tert-butylhydroquinone; GST, glutathione S-transferase; NQO1, NADPH quinone oxidoreductase-1; ARE, antioxidant response element; Nrf2, nuclear factor erythroid 2-related factor 2; dnArnt, dominant negative aryl hydrocarbon receptor nuclear translocator; NAC, N-acetyl-l-cysteine; PCR, polymerase chain reaction; DMSO, dimethyl sulfoxide; EROD, ethoxyresorufin O-deethylase.
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↵1 T.D.S. and C.K. contributed equally to this work and should both be considered first authors.
- Received February 6, 2006.
- Accepted March 28, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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