Interactions of rutaecarpine alkaloids with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver

Abstract

Rutaecarpine alkaloids have the capacity to inhibit specific 2,3,7,8-[1,6-3H]tetrachlorodibenzo-p-dioxin (TCDD) binding in rat liver cytosol, as analysed by electrofocusing in polyacrylamide gel. The IC50 value for binding of 7,8-dehydrorutaecarpine was estimated to approximately 7 nM indicating a high-affinity interaction, whereas rutaecarpine appeared less active (IC50 approximately 110 nM). These findings are of interest in view of the fact that analogues to these compounds may be formed following UV-irradiation of tryptophan and that such photo-products have been suggested to constitute (the) endogenous ligand(s) for the TCDD receptor. As further support of this notion, the rutaecarpine alkaloids investigated could be fitted into a rectangle of 6.8 x 13.7 A, a characteristic common for most high affinity ligands of the TCDD receptor hitherto studied. In view of their structural similarity to dehydrorutaecarpine and the agreement of their mol. wt with that of the photoproduct with the highest affinity for the TCDD receptor, we suggest deaza-analogues of dehydrorutaecarpine to represent possible candidates for the endogenous TCDD receptor ligand.

Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife

“…The Ah receptor agonist and antagonist activities of indole-3-carbinol have been reported (204)(205)(206). Perinatal exposure of pregnant rats to indole-3-carbinol resulted in reproductive abnormalities in male rat offspring, which were also elicited by TCDD in the same study.…”

Pharmacokinetics and Tissue Disposition of Indole-3-carbinol and Its Acid Condensation Products after Oral Administration to Mice

“…It has been shown in vitro to bind with high affinity to the Ah receptor (37) and transcriptionally activate the CYP1A1 gene (38). Taking into account the variation in I3C dosage between studies, the levels of ICZ in the liver reported in this study are higher than those reported previously (18,39).…”

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…To possess strong Ah receptor binding affinity, the molecules must fit into a rectangle with the approximate size of 6.8 × 13.7 Å (Gillner et al 1985). Another important structural requirement for Ah receptor binding is the presence of substructures such as the bay region that are also linked to metabolism.…”