TY - JOUR
T1 - 6-substituted-1,3,8-trichlorodibenzofurans as 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonists in the rat
T2 - structure activity relationships
AU - Astroff, B.
AU - Safe, S.
N1 - Funding Information:
The financial assistance of the National Institutes of Health (ES03843) and the Texas Agricultural Experiment Station is gratefully acknowledged. S. Safe is a Burroughs Wellcome Toxicology Scholar.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1989/12/15
Y1 - 1989/12/15
N2 - The activities of several 6-substituted-1,3,8-trichlorodibenzofurans (CDFs) as partial antagonists of the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities in the rat by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were structure-dependent. Treatment of the rats with TCDD (16 nmol/kg), the 6-substituted-1,3,8-triCDFs (50 μmol/kg) and TCDD plus the 6-substituted-1,3,8-triCDFs showed that most of the substituted congeners were either inactive (6-methyl, ethyl, propyl, i-propyl, t-butyl) or weak (6-cyclohexyl, nitro) inducers of AHH and EROD activities, whereas TCDD caused and 8.1- and 58-fold induction of these enzyme activities respectively. In the co-administration studies, the 6-methyl, propyl, ethyl, isopropyl and t-butyl analogs partially antagonized the induction of the monooxygenase enzyme activities by TCDD, whereas, the 6-cyclohexyl and 6-nitro-1,3,8-triCDFs exhibited minimal activity as TCDD antagonists. The Ah receptor binding affinities of the 6-substituted compounds were determined in a series of in vitro competitive binding studies using [3H]TCDD as the radioligand. Analysis of the data by Scatchard and Dixon plots showed that the avidities for the Ah receptor by the 6-substituted-1,3,8-triCDFs followed the order 6-methyl > 6-t-butyl > 6-i-propyl > 6-propyl ≈ 6-ethyl > 6-cyclohexyl > 6-nitro-1,3,8-triCDF. In addition there was a good correlation between the in vitro binding avidities and Ki values for these compounds and their in vivo activity as partial antagonists of the induction of AHH and EROD activities by TCDD. The results suggested that the 6-substituted-1,3,8-triCDFs competitively displaced TCDD from the Ah receptor and this interaction may play a role in the mechanism of action of this class of TCDD antagonists.
AB - The activities of several 6-substituted-1,3,8-trichlorodibenzofurans (CDFs) as partial antagonists of the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities in the rat by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were structure-dependent. Treatment of the rats with TCDD (16 nmol/kg), the 6-substituted-1,3,8-triCDFs (50 μmol/kg) and TCDD plus the 6-substituted-1,3,8-triCDFs showed that most of the substituted congeners were either inactive (6-methyl, ethyl, propyl, i-propyl, t-butyl) or weak (6-cyclohexyl, nitro) inducers of AHH and EROD activities, whereas TCDD caused and 8.1- and 58-fold induction of these enzyme activities respectively. In the co-administration studies, the 6-methyl, propyl, ethyl, isopropyl and t-butyl analogs partially antagonized the induction of the monooxygenase enzyme activities by TCDD, whereas, the 6-cyclohexyl and 6-nitro-1,3,8-triCDFs exhibited minimal activity as TCDD antagonists. The Ah receptor binding affinities of the 6-substituted compounds were determined in a series of in vitro competitive binding studies using [3H]TCDD as the radioligand. Analysis of the data by Scatchard and Dixon plots showed that the avidities for the Ah receptor by the 6-substituted-1,3,8-triCDFs followed the order 6-methyl > 6-t-butyl > 6-i-propyl > 6-propyl ≈ 6-ethyl > 6-cyclohexyl > 6-nitro-1,3,8-triCDF. In addition there was a good correlation between the in vitro binding avidities and Ki values for these compounds and their in vivo activity as partial antagonists of the induction of AHH and EROD activities by TCDD. The results suggested that the 6-substituted-1,3,8-triCDFs competitively displaced TCDD from the Ah receptor and this interaction may play a role in the mechanism of action of this class of TCDD antagonists.
KW - 2,3,7,8-TCDD
KW - Ah receptor
KW - Partial antagonism
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U2 - 10.1016/0300-483X(89)90198-4
DO - 10.1016/0300-483X(89)90198-4
M3 - Article
C2 - 2631297
AN - SCOPUS:0024307356
VL - 59
SP - 285
EP - 296
JO - Toxicology
JF - Toxicology
SN - 0300-483X
IS - 3
ER -