title: Activation of the human Ah receptor by aza-polycyclic aromatic hydrocarbons and their halogenated derivatives.
abstract: Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor through which dioxins and carcinogenic polycyclic aromatic hydrocarbons cause altered gene expression and toxicity. Ten aza-polycyclic aromatic hydrocarbons (aza-PAHs), consisting of nitrogen substituted naphthalenes, phenanthrenes, chrysenes, and benzo[a]pyrenes (BaPs), were subjected to analysis of their structure-activity relationships as an AhR ligand by using a yeast AhR signaling assay, in which AhR ligand activity was evaluated as lacZ units. Most of the aza-PAHs showed similar or more potent AhR ligand activities than the corresponding parent PAHs. About a 100-fold increased in ligand activity was observed in 10-azaBaP compared with BaP. Halogen-substitution effects on AhR ligand activity in aza-polycyclic aromatics were also investigated with quinoline, benzo[f]quinoline (BfQ), benzo[h]quinoline (BhQ) and 1,7-phenanthroline (1,7-Phe). Position-specific induction of AhR ligand activity was observed in aza-tricyclic aromatic compounds, BfQ, BhQ, and 1,7-Phe, and the ratio of the ligand activities (lacZ units/microM) of monochlorinated and monobrominated aza-tricyclic aromatic compounds to those of the corresponding parent non-halogenated compounds ranged from 2.2- to 254-fold. Greatest enhancement of ligand activity was observed in 2-brominated BfQ (2-Br-BfQ), and its ligand activity was higher than that of BaP. These results suggest that even monohalogenation markedly enhances AhR ligand activity in aza-PAHs.
authors.affiliation: Faculty of Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Nagoya, Japan. saeki@phar.nagoya-cu.ac.jp
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Saeki
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Kato
authors.forename: Katsuya
authors.initials: K
authors.lastname: Yamada
authors.forename: Takaharu
authors.initials: T
authors.lastname: Mizutani
authors.forename: Saburo
authors.initials: S
authors.lastname: Matsui
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukuhara
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
mesh_terms: D001372:Aza Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006846:Hydrocarbons, Halogenated / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism*
chemical_list: D001372:Aza Compounds; D006846:Hydrocarbons, Halogenated; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon