In the daily life, we are exposed to a wide range of environmental pollutants. In particular, dioxins and dioxin-like chemicals are contained in foods and polluted air, and these toxic substances are taken mainly through ingestion and respiration. Cigarette smoke also contains high levels of dioxinlike pollutants that trigger the similar signaling pathway to that of dioxins in vitro and in vivo.
1)Dioxins and dioxin-like substances cause a diverse range of species-and tissue-specific toxicities including carcinogenicity, immunotoxicity, endocrine dysregulation, and reproductive/developmental abnormalities.2,3) Previous reports showed that toxic effects of these pollutants are mediated by the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor. 4) When cells are exposed to these toxic substances, the toxicants pass through the cell membrane and bind to the cytosolic AhR. Subsequently, the AhR-ligands translocate into the nucleus and heterodimerize with the AhR nuclear translocator. These complexes then bind to the xenobiotic responsive element [XRE, also called dioxin responsive element (DRE)], leading to transcriptional induction of dioxin-responsive genes including cytochrome P450 1A1 (CYP1A1). 5) Previous investigation using AhR-null mutant mice confirmed a critical role of AhR in the toxic effects of dioxins.6) Furthermore, constitutive activation of AhR via genetic manipulation caused malignant tumors and immune abnormality in mice even without exposure to xenobiotic ligands. 7,8) Savouret et al. also indicated that activation of AhR by xenobiotic ligands may be a fundamental trigger for cardiovascular diseases.9) Of note, cigarette smoke, a strong activator of AhR, 1) is one of the most famous risk factors for cancers and cardiovascular diseases. Based on this current concept and knowledge, development of AhR antagonists is important for prevention and treatment of AhR-associated diseases caused by dioxins and other xenobiotic ligands.As described, we recently reported that cigarette smoke contains high levels of agonists for AhR using a cell-based reporter assay. Using reporter transgenic mice, we also provided in vivo evidence that exposure of the mice to cigarette smoke causes significant, sustained activation of AhR. 1) Cigarette smoke is known to cause a variety of pathologies including cancers, obstructive pulmonary diseases, atherosclerosis, cardiovascular/cerebrovascular diseases and developmental/reproductive abnormalities. 10) Many of these pathologies are also caused by dioxins and dioxin-like chemicals. 3,9) The fact that cigarette smoke exhibited high levels of the dioxin-like potential for AhR activation suggested a possibility that the health problems known in smokers are, at least in part, due to the potential of cigarette smoke to activate the AhR-XRE/DRE pathway. Development of AhR antagonists may, therefore, also be useful for prevention of cigarette smoke-related disorders in active and passive smokers. Towards this goal, we aimed in the present study at seeking for ...