Carbaryl, a carbamate insecticide, is a ligand for the hepatic Ah (dioxin) receptor.
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of a variety of hydrophobic natural and synthetic chemicals, including the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). Induction of CYP1A1 gene expression is one such response that is known to be regulated by the AhR complex. It was recently reported (Ledirac et al., Toxicol. Appl. Pharmacol. 144, 177-182, 1997) that, although carbaryl, a carbamate insecticide, can induce AhR-dependent expression of CYP1A1, it was not an AhR ligand. Since this apparent ligand-independent activation of the AhR is difficult to reconcile given what is known about the mechanism of AhR action, we have examined the ability of carbaryl to stimulate the AhR signaling pathway. Not only was dioxin responsive element-driven luciferase gene expression induced by carbaryl in stably transfected mouse, rat, guinea pig, and human cells, gel retardation analysis revealed that carbaryl stimulated AhR transformation and DNA binding in vitro and in cells in culture. Dose-response experiments revealed that carbaryl was 300,000-fold less potent that the prototypical inducer, TCDD, in both inducing luciferase gene expression and stimulating AhR transformation and DNA binding in vitro, suggesting that carbaryl itself was the inducing agent. The identification of carbaryl as an AhR ligand was demonstrated by its ability to competitively inhibit [3H]-TCDD to the guinea pig hepatic cytosolic AhR. Our results confirm that carbaryl is both a weak AhR ligand and inducer of AhR-dependent gene expression and argue against its proposed ligand-independent mechanism of AhR activation.
Denison
M S
MS
Department of Environmental Toxicology, University of California, Davis 95616-8588, USA. msdenison@ucdavis.edu
Phelan
D
D
Winter
G M
GM
Ziccardi
M H
MH
D000818:Animals; D001667:Binding, Competitive; D012721:Carbaryl / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter; D006168:Guinea Pigs; D006801:Humans; D007306:Insecticides / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004147:Dioxins; D007306:Insecticides; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D012721:Carbaryl