Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms
Introduction
Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) are industrial compounds or by-products of industrial and combustion processes that have been identified in almost every component of the global ecosystem including fish, wildlife human adipose tissue, milk and serum (Safe, 1995). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic halogenated hydrocarbon, induces a broad spectrum of biochemical and toxic responses in experimental animals and mammalian cells in culture and many of these responses are also dependent on the target organ, age, sex, species and strain of laboratory animal. Poland et al. (1976)initially discovered that TCDD and related compounds bound to an intracellular cytosolic protein designated as the aryl hydrocarbon receptor (AhR). Subsequent studies in several laboratories have demonstrated that the AhR is a ligand-activated nuclear transcripter factor which binds with high affinity to TCDD (KD<1 nM); however, an endogenous ligand has not been identified. The nuclear AhR complex is a heterodimer containing the AhR and AhR nuclear translocater (Arnt) proteins which are members of the basic helix–loop–helix family of nuclear transcription factors. AhR-mediated transactivation was initially investigated using the CYP1A1 gene promoter as a model, and ligand-induced expression of this gene requires binding of the nuclear AhR complex with distal dioxin responsive elements (DREs) that contain a core pentanucleotide sequence required for binding the AhR complex and flanking sequences necessary for transactivation (Whitlock, 1993):
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AhR-mediated antiestrogenic activities
TCDD and related compounds modulate several endocrine response pathways; for example, in the rodent uterus, TCDD inhibits the following 17β-estradiol (E2)-induced responses (reviewed in Safe, 1995): uterine wet weight increase, peroxidase activity, progesterone receptor (PR) binding, epidermal growth factor (EGF) receptor binding, fos and EGF receptor mRNA levels. TCDD and related compounds did not bind the uterine estrogen receptor (ER) or progesterone receptor (PR); however, the AhR was
AhR-mediated antiestrogenicity: molecular mechanisms
Inhibition of E2- and growth factor-induced proliferation of breast cancer cells and mammary tumor growth by AhR agonists may involve multiple pathways (Safe, 1995). For example, TCDD causes a rapid downregulation of nuclear ER levels and this is accompanied by induction of CYP1A1 resulting in rapid oxidative metabolism of E2. Both of these pathways may contribute to the observed antiestrogenic responses; however, there is evidence that other pathways are also involved. Several E2-induced
Development of AhR-based antiestrogens for treatment of breast cancer
Our research has also focused on identifying AhR agonists which exhibit low toxicity but relatively high antiestrogenic and antitumorigenic activities. Alternate substituted (1,3,6,8- and 2,4,6,8-) PCDFs containing at least one alkyl substituted were initially synthesized as potential AhR agonists. 6-Methyl-1,3,8-triCDF (6-MCDF) was utilized as a prototype and results of both in vivo and in vitro studies showed that 6-MCDF partially inhibited TCDD-induced hepatic CYP1A1 and CYP1A2 (rats), and
Acknowledgements
The financial assistance of the Welch Foundation, the National Institutes of Health (ES04167, ES09106 and CA64801), Avax Technologies (Kansas City), and the State of Texas Advanced Technology Program are gratefully acknowledged.
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