Regulation of CYP1A1 gene expression by the antioxidant tert-butylhydroquinone.
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.
Schreiber
Thomas D
TD
Institute of Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Tübingen, Germany.
Köhle
Christoph
C
Buckler
Felicitas
F
Schmohl
Stefan
S
Braeuning
Albert
A
Schmiechen
Alexander
A
Schwarz
Michael
M
Münzel
Peter A
PA
D000975:Antioxidants / Q000494:pharmacology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D009154:Mutation; D010078:Oxazines / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D014162:Transfection
D000975:Antioxidants; D006873:Hydroquinones; D010078:Oxazines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C007649:ethoxyresorufin; C018855:2-tert-butylhydroquinone; D019363:Cytochrome P-450 CYP1A1; D000077185:Resveratrol