Comparison of acute toxicities of indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons are environmental toxicants that act via the AH receptor (AHR). In vitro studies have demonstrated that some indole derivatives present in cruciferous vegetables also bind to the AHR. One of the highest AHR binding affinities is exhibited by indolo[3,2-b]carbazole (ICZ). Since exposure to these dietary indoles is quantitatively far larger than that to halogenated aromatic compounds, their potential toxic risks have raised concern. In the present study, we compared the effects of ICZ with those of a single dose of 20 μg/kg TCDD in the most TCDD-sensitive rat strain (Long–Evans [Turku AB]) (L-E). Whereas TCDD elicited the expected toxicity syndrome, ICZ, either as a single subcutaneous dose (63.5, 127 or 508 μg/kg) or with repeated sc dosing (508 μg/kg for 5 days) failed to reproduce any toxic impacts of TCDD. Furthermore, a simultaneous ICZ treatment (63.5 or 127 μg/kg for 10 days) did not interfere with TCDD (20 μg/kg; single exposure) action. A moderate hepatic induction of CYP1A1 could be triggered by repeated intragastric administration of ICZ (127 μg/kg for 4 days, the last treatment 2.5 h prior to termination). In control experiments in a reconstituted yeast system, ICZ potently and dose-dependently activated L-E rat AHR function demonstrating that it represents a bona fide high-affinity ligand for the rat receptor in vivo. Thus, the present study does not support the view that dietary exposure to ICZ would present a hazard of AHR-mediated adverse health effects to humans.