TY - JOUR
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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U2 - 10.1016/0045-6535(92)90093-7
DO - 10.1016/0045-6535(92)90093-7
M3 - Article
AN - SCOPUS:0027055324
SN - 0045-6535
VL - 25
SP - 967
EP - 973
JO - Chemosphere
JF - Chemosphere
IS - 7-10
ER -