Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin.
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related chemicals. Although no endogenous physiological ligand for the AhR has yet been described, persistent expression of hepatic CYP1A1 gene expression (an AhR-dependent response) in congenitally jaundiced Gunn rats indirectly 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 luciferase gene expression in stably transfected mouse, guinea pig, rat, and human cells was induced by treatment with physiological concentrations of BR. Biliverdin (BV), the metabolic precursor of bilirubin, also induced luciferase activity in all species. BR and BV not only stimulated AhR transformation and DRE binding in vitro andin cells in culture, but competitive inhibition of [3H]TCDD-specific binding to the cytosolic AhR revealed that these chemicals are AhR ligands. The significantly greater inducing potency of these chemicals in intact cells, compared to their ligand binding and AhR transformation potency in vitro, suggests that BR and BV may also be converted within the cell to a more potent activator(s). Our results demonstrate that the heme degradation products BR and BV are AhR ligands which can regulate the AhR-dependent gene expression pathway.
Department of Environmental Toxicology, University of California, Davis, California, 95616, USA.
D
D
Phelan
G M
GM
Winter
W J
WJ
Rogers
J C
JC
Lam
M S
MS
Denison
D000818:Animals; D001663:Bilirubin / Q000378:metabolism / Q000494:pharmacology*; D001664:Biliverdine / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011911:Rats, Gunn; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014407:Tumor Cells, Cultured
D004147:Dioxins; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D004247:DNA; D001664:Biliverdine; D001663:Bilirubin