Antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - induced cyp1A1 gene expression by 6-methyl-1,3,8-trichlorodibenzofuran (MCDF): Mechanistic studies

Mark Merchant; Valerie Morrison; Stephen Safe

doi:10.1016/0045-6535(92)90093-7

Antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - induced cyp1A1 gene expression by 6-methyl-1,3,8-trichlorodibenzofuran (MCDF): Mechanistic studies

Mark Merchant, Valerie Morrison, Stephen Safe

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Treatment of rat hepatoma H-4-II E cells with 10^-9 M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in maximal induction of cytochrome P4501A1-dependent ethoxyresorufin O-deethylase (EROD) activity. In contrast, 10^-6 M 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was relatively inactive as an inducer. Cotreatment with TCDD (10^-9 M) and MCDF (10^-8, 10^-7, 10^-6 M) resulted in a concentration-dependent antagonism of EROD induction. In addition, MCDF caused a concentration-dependent decrease in TCDD-induced CYP1A1 mRNA levels. In a parallel study, MCDF reduced the accumulation of transcriptionally active nuclear [³H]TCDD:Ah receptor complexes. Receptor competition studies with freshly prepared Sprague-Dawley rat cytosol revealed that MCDF competes with [³H]TCDD for Ah receptor binding sites (EC₅₀ ≈ 140 nM). These results suggest that MCDF antagonizes TCDD-mediated induction of CYP1A1 gene expression by competition for the Ah receptor and by decreasing the accumulation of transcriptionally active nuclear Ah receptor complexes.

Original language	English (US)
Pages (from-to)	967-973
Number of pages	7
Journal	Chemosphere
Volume	25
Issue number	7-10
DOIs	https://doi.org/10.1016/0045-6535(92)90093-7
State	Published - 1992

ASJC Scopus subject areas

Environmental Engineering
Environmental Chemistry
General Chemistry
Pollution
Health, Toxicology and Mutagenesis

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10.1016/0045-6535(92)90093-7

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title = "Antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - induced cyp1A1 gene expression by 6-methyl-1,3,8-trichlorodibenzofuran (MCDF): Mechanistic studies",

abstract = "Treatment of rat hepatoma H-4-II E cells with 10-9 M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in maximal induction of cytochrome P4501A1-dependent ethoxyresorufin O-deethylase (EROD) activity. In contrast, 10-6 M 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was relatively inactive as an inducer. Cotreatment with TCDD (10-9 M) and MCDF (10-8, 10-7, 10-6 M) resulted in a concentration-dependent antagonism of EROD induction. In addition, MCDF caused a concentration-dependent decrease in TCDD-induced CYP1A1 mRNA levels. In a parallel study, MCDF reduced the accumulation of transcriptionally active nuclear [3H]TCDD:Ah receptor complexes. Receptor competition studies with freshly prepared Sprague-Dawley rat cytosol revealed that MCDF competes with [3H]TCDD for Ah receptor binding sites (EC50 ≈ 140 nM). These results suggest that MCDF antagonizes TCDD-mediated induction of CYP1A1 gene expression by competition for the Ah receptor and by decreasing the accumulation of transcriptionally active nuclear Ah receptor complexes.",

author = "Mark Merchant and Valerie Morrison and Stephen Safe",

note = "Funding Information: ACKNOWLEDGEMENTS The financial assistance of the National Institutes of Health (ES-03843) and the Texas Agricultural Experiment Station are gratefully acknowledged. S. Safe is a Burroughs Wellcome Toxicology Scholar. Copyright: Copyright 2014 Elsevier B.V., All rights reserved.",

year = "1992",

doi = "10.1016/0045-6535(92)90093-7",

language = "English (US)",

volume = "25",

pages = "967--973",

journal = "Chemosphere",

issn = "0045-6535",

publisher = "Elsevier Ltd",

number = "7-10",

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T1 - Antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - induced cyp1A1 gene expression by 6-methyl-1,3,8-trichlorodibenzofuran (MCDF)

T2 - Mechanistic studies

AU - Merchant, Mark

AU - Morrison, Valerie

AU - Safe, Stephen

N1 - Funding Information: ACKNOWLEDGEMENTS The financial assistance of the National Institutes of Health (ES-03843) and the Texas Agricultural Experiment Station are gratefully acknowledged. S. Safe is a Burroughs Wellcome Toxicology Scholar. Copyright: Copyright 2014 Elsevier B.V., All rights reserved.

PY - 1992

Y1 - 1992

N2 - Treatment of rat hepatoma H-4-II E cells with 10-9 M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in maximal induction of cytochrome P4501A1-dependent ethoxyresorufin O-deethylase (EROD) activity. In contrast, 10-6 M 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was relatively inactive as an inducer. Cotreatment with TCDD (10-9 M) and MCDF (10-8, 10-7, 10-6 M) resulted in a concentration-dependent antagonism of EROD induction. In addition, MCDF caused a concentration-dependent decrease in TCDD-induced CYP1A1 mRNA levels. In a parallel study, MCDF reduced the accumulation of transcriptionally active nuclear [3H]TCDD:Ah receptor complexes. Receptor competition studies with freshly prepared Sprague-Dawley rat cytosol revealed that MCDF competes with [3H]TCDD for Ah receptor binding sites (EC50 ≈ 140 nM). These results suggest that MCDF antagonizes TCDD-mediated induction of CYP1A1 gene expression by competition for the Ah receptor and by decreasing the accumulation of transcriptionally active nuclear Ah receptor complexes.

AB - Treatment of rat hepatoma H-4-II E cells with 10-9 M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in maximal induction of cytochrome P4501A1-dependent ethoxyresorufin O-deethylase (EROD) activity. In contrast, 10-6 M 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was relatively inactive as an inducer. Cotreatment with TCDD (10-9 M) and MCDF (10-8, 10-7, 10-6 M) resulted in a concentration-dependent antagonism of EROD induction. In addition, MCDF caused a concentration-dependent decrease in TCDD-induced CYP1A1 mRNA levels. In a parallel study, MCDF reduced the accumulation of transcriptionally active nuclear [3H]TCDD:Ah receptor complexes. Receptor competition studies with freshly prepared Sprague-Dawley rat cytosol revealed that MCDF competes with [3H]TCDD for Ah receptor binding sites (EC50 ≈ 140 nM). These results suggest that MCDF antagonizes TCDD-mediated induction of CYP1A1 gene expression by competition for the Ah receptor and by decreasing the accumulation of transcriptionally active nuclear Ah receptor complexes.

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Antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - induced cyp1A1 gene expression by 6-methyl-1,3,8-trichlorodibenzofuran (MCDF): Mechanistic studies

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