Activation of the human Ah receptor by aza-polycyclic aromatic hydrocarbons and their halogenated derivatives.
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.
Saeki
Ken-ichi
K
Faculty of Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Nagoya, Japan. saeki@phar.nagoya-cu.ac.jp
Matsuda
Tomonari
T
Kato
Taka-aki
TA
Yamada
Katsuya
K
Mizutani
Takaharu
T
Matsui
Saburo
S
Fukuhara
Kiyoshi
K
Miyata
Naoki
N
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*
D001372:Aza Compounds; D006846:Hydrocarbons, Halogenated; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon