6-methyl-1,3,8-trichlorodibenzofuran and related compounds as 2,3,7,8-TCDD antagonists and antiestrogens /
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| Other Authors: | , , |
| Format: | Thesis Book |
| Language: | English |
| Published: |
1989.
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| Subjects: | |
| Online Access: | ProQuest, Abstract Link to OAKTrust copy Link to ProQuest copy |
| Abstract: | In addition to being one of the most toxic chemicals known, 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) is the most potent inducer of rat liver microsomal cytochrome P-450IA1 and related hepatic monooxygenases. Previous studies have demonstrated that a high affinity, low capacity cytosolic receptor (the Ah receptor) mediates the activity of TCDD to induce biologic and toxic responses in the rat. 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) binds with moderate affinity to the Ah receptor (EC[50] 10 nM) but is a weak Ah receptor agonist. Cotreatment of male Long Evans rats with MCDF (50 μmol/kg) and a dose of TCDD that causes a near-maximal induction of hepatic microsomal monooxygenase activities resulted in a significant inhibition of these activities and the ability of TCDD to induce cytochrome P-450IA1 and P-450IA2. The partial antogonism produced by 50 μmol/kg MCDF could be partially overcome by doubling the dosage of TCDD from 16 to 32 nmol/kg. MCDF similarly antagonized the TCDD-mediated thymic atrophy and body weight loss in female Sprague Dawley rats coadministered TCDD plus MCDF. The avidities of several 6-substituted-l,3,8-trichlorodibenzofurans (CDFs) to bind to the Ah receptor and as partial antagonists of the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities by TCDD were structure-dependent. Comparative antiestrogenic activities of TCDD and MCDF to decrease uterine and hepatic cytosolic and nuclear estrogen (ERc and ERn) and progesterone (PRc and PRn) receptors exhibited a dose-response relationship. Similarly, both TCDD (0.256 μmol/kg) and MCDF (100 μmol/kg) decreased both constitutive and estradiol-induced uterine peroxidase activity, and epidermal growth factor receptor levels. Structure-activity studies using 2,3,4,7,8-PeCDF and 1,2,4,7,8-PeCDD and their affect on uterine wet weight and uterine peroxidase activity suggest that the antiestrogenic effects of this class of compounds are mediated by the Ah receptor. The relative TCDD/MCDF potencies for the reduction of uterine ERc, ERn, PRc and PRn levels were 293, 569, 560, and 459, respectively. In contrast, the relative potencies for AHH and EROD induction are 158,850 and 214,300, respectively. |
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| Item Description: | Typescript (photocopy). Vita. "Major subject: Toxicology." |
| Physical Description: | xvi, 176 leaves : illustrations ; 29 cm |
| Bibliography: | Includes bibliographical references. |