AH RECEPTOR SIGNALING PATHWAYS

The aryl hydrocarbon (Ah) receptor has occupied the attention of toxic ologists for over two decades. Interest arose from the early observati on that this soluble protein played key roles in the adaptive metaboli c response to polycyclic aromatic hydrocarbons and in the toxic mechan ism of halogenated dioxins and dibenzofurans. More recent investigatio ns have provided a fairly clear picture of the primary adaptive signal ing pathway, from agonist binding to the transcriptional activation of genes involved in the metabolism of xenobiotics. Structure-activity s tudies have provided an understanding of the pharmacology of this rece ptor; recombinant DNA approaches have identified the enhancer sequence s through which this factor regulates gene expression; and functional analysis of cloned cDNAs has allowed the characterization of the major signaling components in this pathway. Our objective is to review the Ah receptor's role in regulation of xenobiotic metabolism and use this model as a framework for understanding the less well-characterized me chanism of dioxin toxicity. In addition, it is hoped that this informa tion can serve as a model for future efforts to understand an emerging superfamily of related signaling pathways that control biological res ponses to an array of environmental stimuli.