ACTIVATION OF THE AH RECEPTOR SIGNAL-TRANSDUCTION PATHWAY BY BILIRUBIN AND BILIVERDIN

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptio n factor that mediates many of the biological and toxicological action s of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related ch emicals. Although no endogenous physiological ligand for the AhR has y et been described, persistent expression of hepatic CYP1A1 gene expres sion (an AhR-dependent response) in congenitally jaundiced Gunn rats i ndirectly supports the existence of such a ligand(s) in these animals, High plasma levels of the heme degradation product bilirubin (BR) in these animals prompted us to evaluate whether BR is an endogenous AhR agonist, Expression of dioxin responsive element (DRE)-driven lucifera se gene expression in stably transfected mouse, guinea pig, rat, and h uman cells was induced by treatment with physiological concentrations of BR. Biliverdin (BV), the metabolic precursor of bilirubin, also ind uced luciferase activity in all species. BR and BV not only stimulated AhR transformation and DRE binding in vitro and in cells in culture, but competitive inhibition of [H-3]TCDD-specific binding to the cytoso lic AhR revealed that these chemicals are AhR ligands. The significant ly greater inducing potency of these chemicals in intact cells, compar ed to their ligand binding and AhR transformation potency in vitro, su ggests that BR and BV may also be converted within the cell to a merle potent activator(s). Our results demonstrate that the heme degradatio n products BR and BV are AhR ligands which can regulate the AhR-depend ent gene expression pathway. (C) 1998 Academic Press.