Polychlorinated dibenzofurans as 2,3,7,8-tcdd antagonists: In vitro inhibition of monooxygenase enzyme induction

2,4,6,8- and 1,3,6,8-tetrachlorodibenzofuran (TCDF) competitively displace [³H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) from the rat cytosolic receptor protein and their EC₅₀ values were 1.5 × 10^-6 and 1.25 x 10^-7 M, respectively. In contrast to their relatively high binding avidities these TCDF isomers were poor inducers of benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase in rat hepatoma H-4-II E cells in culture (EC₅₀ > 10^-5 M). Coadministration of different concentrations of 2,4,6,8- and 1,3,6,8-TCDF (10^-5, 10^-6 and 10^-7 M) with 2 × 10^-10 M, 2,3,7,8-TCDD (a dose which elicits 80% of the maximal induction response) resulted in significant decreases in the expected (additive) induction of benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase by the mixture. Thus the partial agonists, 1,3,6,8- and 2,4,6,8-TCDF, antagonize the receptor-mediated enzyme induction activity of 2,3,7,8-TCDD presumably via competitive displacement of 2,3,7,8-TCDD from the receptor protein. In contrast, coadministration of 2,3,7,8-TCDF and 2,3,7,8-TCDD gave additive enzyme induction responses. The identification of the 2,3,7,8-TCDD antagonists represents a new class of halogenated aryl hydrocarbons.