Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Level 5 - mechanism / opinion, no new human data
Bench and rodent in vitro/in vivo mechanistic study
PubMed 1658785 · doi:10.1073/pnas.88.21.9543
What was done
The authors examined the generation and binding affinity of acid condensation products of indole-3-carbinol (I3C) to the aromatic hydrocarbon (Ah) responsiveness-receptor using C57BL/6J mouse liver cytosol. They quantified in vitro and in vivo (following oral intubation) molar yields of I3C condensation products, focusing on indolo[3,2-b]carbazole (ICZ). They also measured ICZ-mediated induction of cytochrome P4501A1 via ethoxyresorufin O-deethylase activity in murine hepatoma Hepa 1c1c7 cells and compared its receptor affinity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
What was found
Major acid condensation products of I3C had Ah receptor Kd values between 22 nM and 90 nM, with in vitro and in vivo molar yields of 0.1% to 6%. ICZ formed at yields around 0.01% in vitro and in vivo. ICZ exhibited an Ah receptor Kd of 190 pM and an EC50 of 269 nM for CYP1A1 induction in cell culture, displaying a binding affinity 3.7 x 10(-2) times that of TCDD.
Why it matters
The findings establish a chemical mechanism for the enzyme-inducing and Ah-receptor-activating properties of dietary I3C from Brassica vegetables, demonstrating that acid-catalyzed condensation in the stomach generates potent receptor agonists.
Limits
The study was conducted exclusively in mouse cytosol, murine cell lines, and rodents; human in vivo kinetics were not measured. Sample sizes, animal numbers, and variance metrics were not reported in the abstract. Clinical and long-term toxicological outcomes were not evaluated.
Cited by
- supports Indole-3-carbinol (I3C) and diindolylmethane (DIM) can polymerize into dimers or tetramers that structurally resemble dioxin.