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Mechanisms of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds
Mechanisms of action of two, three, seven, eight-tetrachlorodibenzo-p-dioxin and related compounds
xvii, 162 leaves : illustrations ; 28 cm.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibited insulin-
like growth factor-I (IGF-I)- /insulin-induced proliferation
of MCF-7 cells. TCDD did not affect the binding affinity of
[1251]IGF-I for the IGF-I receptor but decreased the number
of IGF-1-induced receptor binding sites (Bmax). In contrast,
TCDD alone did not affect Kd and Bmax values for binding of
[12511insulin to the insulin receptor (IR) but decreased the
insulin-induced Kd value for IR-ligand binding and increased
Bmax value in cells cotreated with TCDD and insulin. TCDD
also inhibited insulin-induced c-fos protooncogene expression
and phosphorylation of the IR. In this study, two classes of
compounds, namely, 6-substituted 3,4-benzocoumarins and 2-
substituted phenanthridinones were characterized as aryl
hydrocarbon receptor (AhR) agonists/antagonists and as
inhibitors of CYP IA I -dependent activity in rat hepatoma
H411E and human breast cancer MCF-7 cells. Both classes of
compounds bound to the AhR; however, there was no correlation
between their AhR-binding affinities and CYPIAL induction
potencies in H41IE cells. 6-t-Butyl-3,4-benzocoumarin and 2
phenylphenanthridinone inhibited CYPL Al activity by suicide
inactivation of the protein but did not act as AhR
antagonists in this cell line. In contrast, these two
compounds exhibited AhR antagonist activities and inhibited
induction of CYPIA] gene expression by TCDD in MCF-7 cells.
Thus, the effects of 6-substituted 3,4-benzocoumarins and 2-
substituted phenanthridinones were cell line-dependent.
lndolo[3,2b]carbazole (ICZ) is derived from the natural
product indole-3-carbinol (13C) via acid catalysis and
previous studies have reported that ICZ (and 13C) exhibit AhR
agonist activities, namely, binding to the AhR and induction
this study. Like TCDD and other AhR agonists, ICZ
downregulated nuclear esttogen receptor (ER) and inhibited
E2-induced progesterone receptor (PR) levels, vit-CAT
activity, cell proliferation and [3H]thymidine with [3H]E2
for rat uterine cytosolic ER. Thus ICZ is an unique compound
which exhibits both AhR and ER agonist activities.
In title, symbols and numerals are used.
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