Activation of the aryl hydrocarbon receptor by methyl yellow and related congeners: Structure-activity relationships in halogenated derivatives

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological action of many environmental compounds. Methyl yellow (4-dimethylaminoazobenzene; MY) is a principal azodye, and structurally related compounds were subjected to analysis of structure-activity relationships as AhR ligands by using a yeast AhR signaling assay. The effects of halogen-substitution among 23 halogenated MYs on the AhR ligand activity can be summarized as follows: enhancement by halogen-substitution at the ortho-position (2'- and 6'-position), and reduction by substitution at the para-position (4'-position). The greatest enhancement of the ligand activity was observed in 2',6'-dichlorinated MY (13.5-fold of MY), and its AhR ligand activity was very close to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the present assay system. In the study of compounds structurally related to MY, benzanilide (BA) showed almost the same AhR ligand activity as azobenzene and trans-stilbene. Furthermore, 4'-chlorobenzanilide, in which the length of the molecule is similar to that of MY, enhanced the AhR ligand activity by ortho(2')-chlorine-substitution, and the AhR ligand activity of 2',4'-dichlorobenzanilide was similar to that of 2'-chloro-MY. These results suggest that the amide bond is equivalent to the -N=N- or -CH=CH- double bond for recognition as the ligand by AhR in 1,2-diphenyl-1,2-ene derivatives.