Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of 6-nitro-1,3,8-trichlorodibenzofuran (6-NCDF) caused a dose- and time-dependent increase in uterine wet weight and cytosolic and nuclear estrogen receptor (ER) and progesterone receptor (PR) levels in immature female Sprague-Dawley rats. These estrogenic effects persisted for up to 96 or 144 hr after initial administration of 6-NCDF and could be observed at a dose as low as 2 mumol/kg. In contrast, 6-NCDF (25 mumol/kg) did not increase rat uterine peroxidase activity or epidermal growth factor (EGF) receptor binding activity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), which exhibits a broad spectrum of antiestrogenic effects in the female rat uterus, inhibited the 17 beta-estradiol-induced increase in uterine wet weights, cytosolic and nuclear ER and PR levels, peroxidase activity, and EGF receptor binding activity. In contrast, 2,3,7,8-TCDD inhibited the uterotropic effects caused by 6-NCDF but did not affect the 6-NCDF-induced uterine ER and PR levels. 6-NCDF is a weak inducer of hepatic microsomal ethoxyresorufin O-deethylase activity and competitively binds to the aryl hydrocarbon (Ah) receptor but not the PR or ER. Thus both 6-NCDF and 2,3,7,8-TCDD, two ligands which bind to the Ah receptor, exhibit both partial estrogenic and antiestrogenic properties and serve as useful models for delineating the complex biochemical interactions between the ER and Ah receptor signal transduction pathways.
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PMID:The effect of 6-nitro-1,3,8-trichlorodibenzofuran as a partial estrogen in the female rat uterus. 131 94

In the female Sprague-Dawley rat uterus 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds exhibited a broad spectrum of antioestrogenic responses. For example 2,3,7,8-TCDD inhibited the 17 beta-oestradiol-induced uterine wet weight increase, peroxidase activity, oestrogen and progesterone receptor levels, epidermal growth factor (EGF) receptor binding, and EGF receptor and c-fos protooncogene mRNA levels. The aryl hydrocarbon (Ah) receptor was identified in the rat uterus and the antioestrogenic activities of TCDD and related compounds were structure-dependent. In parallel studies, the effects of TCDD as an antioestrogen in MCF-7 human breast cancer cells was also investigated. TCDD inhibited the 17 beta-oestradiol-induced proliferation of these cells and the secretion of the 34-, 52- and 160-kDa proteins. Treatment of MCF-7 cells with 1 nM [3H]-17 beta-oestradiol resulted in a rapid accumulation of nuclear oestrogen receptor (ER) complexes. Pretreatment of the cells with TCDD caused a rapid decrease in nuclear ER binding activity and immunoreactive protein; moreover, the structure-dependent potencies of TCDD and related compounds as antioestrogens were similar to their Ah receptor binding affinities. TCDD also caused a decrease in nuclear ER levels in wild-type Ah-responsive Hepa 1c1c7 cells but was inactive in Ah non-responsive mutant Hepa 1c1c7 cells. Moreover, in the wild-type cells, both actinomycin D and cycloheximide blocked the effects of TCDD. 6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) has previously been characterized as a TCDD antagonist in rodents and in transformed rodent cell lines. However, like TCDD, MCDF also exhibited a broad spectrum of antioestrogenic activities in both the female Sprague-Dawley rat uterus and MCF-7 cells. MCDF is relatively non-toxic compared to TCDD and is being investigated as a compound which may be clinically useful for the treatment of mammary cancer.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds as antioestrogens: characterization and mechanism of action. 176 14

The present studies examine whether the Ah receptor mediates the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the binding capacity of the hepatic epidermal growth factor (EGF) receptor in congenic strains of C57BL/6J mice that differ only at the Ah locus. The Ah locus is believed to encode the Ah receptor, which mediates the induction of cytochrome P4501A1 by TCDD and appears to mediate many of the toxic effects of TCDD. TCDD produced an 80-90% decrease in the maximum binding capacity (both high and low affinity sites) of the hepatic EGF receptor in female Ah-responsive (Ahb/b) and Ah-nonresponsive (Ahd/d) C57BL/6 mice. However, the ED50 for the effects of TCDD on the binding capacity of the EGF receptor was 10-fold higher in the Ah-nonresponsive mice, compared with the Ah-responsive mice (7 versus 0.7 micrograms/kg). TCDD did not affect the hepatic content of two EGF receptor mRNA transcripts (10 and 6 kb), indicating that the effects on the EGF receptor are not pretranslational. Similarly, TCDD did not affect the hepatic content of mRNA for transforming growth factor-alpha, an alternate ligand for the EGF receptor that is synthesized in the liver. In contrast, TCDD markedly increased the hepatic content of the mRNA for cytochrome P4501A1, which is known to be regulated transcriptionally by TCDD. The ED50 for this effect was 10-fold higher in Ah-nonresponsive mice than in Ah-responsive mice (13 versus 1.3 micrograms/kg). This study indicates that the effects of TCDD on EGF receptor ligand binding are mediated by the Ah receptor. However, unlike the effect of TCDD on cytochrome P4501A1, the effects of TCDD on the EGF receptor do not involve changes in the levels of the mRNA for this protein or changes in the mRNA for transforming growth factor-alpha, an alternate ligand for the EGF receptor.
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PMID:Influence of the Ah locus on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic epidermal growth factor receptor. 184 54

The comparative antiestrogenic effects of 6-methyl-1,3,8-trichlorodibenzofuran (MCDF), 6-t-butyl-1,3,8-trichlorodibenzofuran (triCDF) and 6-cyclohexyl-1,3,8-triCDF were determined in immature female Sprague-Dawley rats. Treatment of the animals with 17 beta-estradiol (0.33 mumol/kg X 2) caused an increase in uterine cytosolic and nuclear estrogen and progesterone receptor levels, uterine peroxidase activity, uterine wet weights and uterine epidermal growth factor (EGF) receptor binding activity and steady state EGF receptor mRNA levels. MCDF and 6-t-butyl-1,3,8-triCDF, two compounds which exhibit moderate aryl hydrocarbon (Ah) receptor binding affinity were also administered (100 mumol/kg) to the female rats in the presence or absence of 17 beta-estradiol. The results of these studies show that both compounds decrease the constitutive and 17 beta-estradiol-induced responses noted above. In contrast, 6-cyclohexyl-1,3,8-triCDF, a congener which exhibits low Ah receptor binding, was inactive as an antiestrogen. These studies clearly demonstrate that selected 6-alkyl-1,3,8-triCDFs elicit a broad spectrum of antiestrogenic activity in immature female rats. Moreover, in contrast to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) which also is a potent antiestrogen, the 6-alkyl-1,3,8-triCDFs are relatively non-toxic and can serve as prototypes for the future development of a new class of antiestrogens with potential for clinical applications.
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PMID:6-Alkyl-1,3,8-trichlorodibenzofurans as antiestrogens in female Sprague-Dawley rats. 194 47

2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are environmental contaminants which mimic many of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Like TCDD, these polychlorinated dibenzofurans (PCDFs) induce hepatic benzo[a]pyrene hydroxylase activity (BPH) and possess high affinity for the Ah receptor. Another similarity of these PCDFs to TCDD is their ability to induce teratogenic effects such as cleft palate and hydronephrosis in mice. Recent studies have shown that TCDD modifies the equilibrium binding kinetics of the rat liver cytosolic glucocorticoid receptor (GRc) and the hepatic plasma membrane epidermal growth factor (EGF) receptor. To gain a better understanding of the action of halogenated hydrocarbons on these cytosolic and membrane-bound receptor systems during pregnancy, we investigated the biochemical effects of PeCDF and HCDF on the binding kinetics of maternal mouse liver GRc and EGF receptors and the induction of BPH activities. Pregnant C57BL/6N mice were treated once daily on gestation Days 10 through 13 with PeCDF (0-30 micrograms/kg) or HCDF (0-300 micrograms/kg). Hepatic [3H]dexamethasone and [125I]EGF equilibrium binding studies indicated that all doses of PeCDF tested (10, 20, and 30 micrograms/kg) significantly reduced the GRc and EGF receptor maximum binding capacities but did not affect the binding affinities of these receptors when compared to corn oil-treated control pregnant mice. Similar effects were observed for doses of HCDF greater than or equal to 100 micrograms/kg. These data suggest that the dibenzofuran-mediated decreases in GRc and EGF receptor binding capacities are similar to those caused by TCDD. Although the mechanism of action is not yet clear, our results indicate that halogenated aromatic compounds in addition to TCDD have profound effects on both steroid and growth factor receptor systems.
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PMID:Decreased ligand binding to the hepatic glucocorticoid and epidermal growth factor receptors after 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran treatment of pregnant mice. 271 74

Our studies have evaluated biochemical changes in placentae from humans exposed to rice oil contaminated with polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) in Taiwan. Placentae were obtained from nonsmoking women 4 to 5 years after the exposure had occurred. The exposed individuals ingested approximately 1 to 3 g PCBs and 5 mg PCDFs, and many exhibited symptoms characteristic of PCB poisoning. This disease was termed "Yu-Cheng" in Chinese. Based on data from experimental animal models, we examined a number of parameters in placentae from control and exposed women, including arylhydrocarbon hydroxylase (AHH) activity, cytochrome P-450 isozymes, epidermal growth factor (EGF) receptor binding properties and actions, and Ah receptor. We also quantified concentrations of various PCB and PCDF congeners known to be present in the contaminated rice oil. Our results revealed a dramatic elevation in placental AHH activity in samples from PCB/PCDF-exposed women. This increase in enzyme activity was associated with a parallel increase in placental microsomal protein immunochemically related to cytochrome P-450 form 6 [derived from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced rabbit lung]. No other cytochrome P-450 isozyme was detected in placental preparations, and the form 6 homolog was found only in placentae from exposed women. EGF receptor-mediated autophosphorylation capacity was significantly diminished in PCB/PCDF placentae, but this effect was not associated with changes in plasma membrane EGF receptor binding properties (Kd and Bmax). The EGF receptor autophosphorylation effect correlated well with the decrease in birthweight observed in offspring of exposed women, suggesting that this biochemical event might provide a good marker of effect for the toxic halogenated aromatics.
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PMID:Placental markers of human exposure to polychlorinated biphenyls and polychlorinated dibenzofurans. 283 96

Improved methods for estimating the shape of the response curve for effects of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are needed in order to evaluate possible adverse health effects of TCDD. A mathematical model has been constructed to describe TCDD-mediated alterations in hepatic proteins in the rat. In this model it was assumed that TCDD mediates increases in the liver concentration of transforming growth factor-alpha (TGF-alpha) by a mechanism which requires the aryl hydrocarbon (Ah) receptor. TGF-alpha subsequently binds to the epidermal growth factor (EGF) receptor, a process which is known to cause internalization of this receptor in hepatocytes. This action is thought to be an early event in the generation of a mitogenic signal. Because TCDD decreases binding of EGF in the livers of intact female rats but not in ovariectomized rats, this effect was further assumed to be dependent on estrogen action. The model postulates Ah receptor-dependent effects on the concentration of cytochrome P450 1A2 (CYP1A2), which is involved in the metabolism of estradiol, and on the concentration of the estrogen receptor. The model also incorporates information on induction of cytochrome P450 1A1 (CYP1A1) by TCDD. The biochemical response curves for all these proteins were hyperbolic (Hill exponents in the equations for their expression were found to be 1), indicating a proportional relationship between target tissue dose and protein concentration at low administered doses of TCDD. The model successfully reproduced the observed tissue distribution of TCDD, the concentrations of CYP1A1 and CYP1A2, and the effects of TCDD on the Ah, estrogen, and EGF receptors over a wide dose range.
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PMID:A mechanistic model of effects of dioxin on gene expression in the rat liver. 851 76