Mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) : interactive effects of TCDD with retinoic acid and substituted flavones /
It was shown in this study that both TCDD and RA elicit a number of common responses in MCF-7 human breast cancer cells, including inhibition of estrogen-induced cell proliferation and [3H]thymidine uptake, inhibition of nuclear ER ligand binding, and binding of nuclear extracts to a [32p]ERE. TCDD...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1996.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=743266821&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | It was shown in this study that both TCDD and RA elicit a number of common responses in MCF-7 human breast cancer cells, including inhibition of estrogen-induced cell proliferation and [3H]thymidine uptake, inhibition of nuclear ER ligand binding, and binding of nuclear extracts to a [32p]ERE. TCDD and RA also decreased steady-state ER MRNA levels in a time-dependent manner. Cotreatment of cells with TCDD plus RA resulted in an additive inhibition of the above responses. TCDD also decreased steady-state RAR(X MRNA levels in MCF-7 cells, and the AhR is required for this response.The structure-dependent AhR agonist/antagonist activities of fourteen 4'- or 3',4'substituted flavones were investigated. All the substituted flavones competitively bind to the rat cytosolic AhR and inhibited TCDD-induced transformation of the cytosolic AhR. All flavones inhibited TCDD-induced EROD activity in MCF-7 cells and this was due, in part, to direct interactions of substituted flavones with CYPIAI substrate-binding sites. The haloflavones (1 gM) were weak inducers of CYPlAl MRNA levels in MCF-7 cells. 4' lodoflavone (0.0 1 and 0. I liM) also inhibited TCDD-induced CYP I A I MRNA levels. 3'methoxy-4'-nitro- and 4'-amino-3'- methoxyflavones (1 and 10 JIM) significantly inhibited TCDD-induced CYPIAI MRNA levels and formation of nuclear 5-7S AhR complex; however, formation of an early eluting specifically bound nuclear AhR cpmplex was not inhibited. The difference between the structure-dependent activity of the substituted flavones and other HAHs as AhR agonists/antagonists and results obtained for 4'amino/nitro-3'-methoxyflavones support the hypothesis that there may be more than one form of the AhR and that different structural classes of ligand may induce different conformations of the AhR complex. TCDD did not affect PRLR binding but decreased PRLR MRNA levels in MCF-7 cells in a time-dependent manner. Estrogen treatment caused a time-dependent induction of PRLR MRNA levels, and TCDD significantly inhibited estrogen-induced PRLR MRNA levels. The results of this study show that PRLR and ER are differentially regulated by TCDD. |
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| Item Description: | Vita. "Major Subject: Toxicology". In title, numerals are used. |
| Physical Description: | xii, 176 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references. |