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.
- enzyme induction
ASJC Scopus subject areas