title: Polychlorinated dibenzofurans as 2,3,7,8-TCDD antagonists: in vitro inhibition of monooxygenase enzyme induction.
abstract: 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 X 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 greater than 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 X 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.
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D004147:Dioxins / Q000037:antagonists & inhibitors*; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects*
chemical_list: D001572:Benzofurans; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; C049040:1,3,6,8-tetrachlorodibenzofuran; C049041:2,4,6,8-tetrachlorodibenzofuran; D010088:Oxidoreductases; D001579:Benzopyrene Hydroxylase; D019363:Cytochrome P-450 CYP1A1