Mechanisms of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds /

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibited insulin-

Bibliographic Details
Main Author:	Liu, Hong, 1964-
Format:	Thesis Book
Language:	English
Published:	[Place of publication not identified] : [publisher not identified] ; 1994.
Subjects:	Major toxicology.
Online Access:	http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=746794931&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD

Description
Summary:	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.
Item Description:	Vita. "Major Subject: Toxicology". In title, symbols and numerals are used.
Physical Description:	xvii, 162 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc.
Bibliography:	Includes bibliographical references.