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.

• Authors: B Keys, J Piskorska-Pliszczynska, S Safe
• Journal: Toxicology letters (Toxicol Lett) Vol. 31 Issue 2 Pg. 151-8 (May 1986) ISSN: 0378-4274 [Print] Netherlands
• PMID: 3012826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Benzofurans
• Dioxins
• Polychlorinated Dibenzodioxins
• Receptors, Aryl Hydrocarbon
• Receptors, Drug
• 1,3,6,8-tetrachlorodibenzofuran
• 2,4,6,8-tetrachlorodibenzofuran
• Oxidoreductases
• Benzopyrene Hydroxylase
• Cytochrome P-450 CYP1A1

Topics

• Animals
• Benzofurans (pharmacology)
• Benzopyrene Hydroxylase (metabolism)
• Binding, Competitive (drug effects)
• Cytochrome P-450 CYP1A1
• Dioxins (antagonists & inhibitors)
• Enzyme Induction (drug effects)
• In Vitro Techniques
• Liver Neoplasms, Experimental (enzymology, metabolism)
• Oxidoreductases (metabolism)
• Polychlorinated Dibenzodioxins (antagonists & inhibitors)
• Rats
• Receptors, Aryl Hydrocarbon
• Receptors, Drug (drug effects)