The aryl hydrocarbon receptor (AhR) mediates a spectrum of adaptive and toxic responses to the environmental contaminant TCDD and related halogenated aromatic hydrocarbons. AhR may also playa role(s) in development, growth, and differentiation of tissues in the absence of an exogenous ligand. The broad range of TCDD toxicity and AhR function suggest that the mechanism of AhR action involves multiple signaling mechanisms. In this study, we examined the interaction of AhR with phenolic antioxidant signal transduction, which involves oxidative signaling. Phenolic antioxidants, such as tert-butylhydroquinone (tBHQ), hydroquinone (HQ), or catechol, induce the expression of CYPlAl in mouse hepalclc7 cells; the induction is enhanced by inhibition of protein synthesis by cycloheximide (CHX) (termed superinduction). Induction by the antioxidants is both concentration and time-dependent. Furthermore, the induction and superinduction require AhR and Arnt, as they are absent in AhR or Arnt defective variant cells, and are mediated through the DRE-containing enhancer of CYP1A1, as they are reconstituted in a CYP1A1 enhancer-luciferase reporter expression system. These findings demonstrate that phenolic antioxidants can activate AhR-mediated gene transcription and suggest interaction of AhR with antioxidant mediated oxidative signaling.
The Toxicologist. Society of Toxicology 41st Annual Meeting and ToxExpo, March 17-21, 2002, Nashville, Tennessee